1
|
Zhu Y, Ali A, Mulinari Dos Santos G, Franciscon JPS, de Molon RS, Goh C, Erovolino E, Theodoro LH, Shrestha A. A Chitosan-based Hydrogel to Modulate Immune Cells and Promote Periodontitis Healing in the High-Fat Diet-induced Periodontitis Rat Model. Acta Biomater 2025:S1742-7061(25)00358-7. [PMID: 40379118 DOI: 10.1016/j.actbio.2025.05.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 05/06/2025] [Accepted: 05/12/2025] [Indexed: 05/19/2025]
Abstract
Periodontitis is a multifactorial inflammatory disease driven by prolonged, dysregulated inflammation between dysbiotic microbiota and the host immune system. Risk factors such as metabolic syndrome exacerbate periodontitis progression through systemic inflammation. Current treatments primarily focus on removing pathogenic dental plaque, but subsequent healing relies mainly on the host immune response. Modulating the local immune environment, particularly dendritic cells (DCs) and T-cells, in periodontitis complicated by metabolic syndrome could enhance the healing process. The objective of this study is to develop a biomaterial-based adjuvant therapy to immunomodulate DCs and T-cells and promote healing in periodontitis complicated by metabolic syndrome. We developed and characterized a chitosan-based thermosensitive injectable self-assembled hydrogel (TISH), which exhibited an interconnected porous structure conducive to cell migration and adhesion. TISH was loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF) and resveratrol (TISH(GR)), enabling sustained release over time. Mechanistically, TISH(GR) suppressed inflammatory signalling pathways (MAPKs and NF-κB) downstream of Toll-like receptor-4 in DCs. In a high-fat diet-induced periodontitis rat model, TISH(GR) administered as an adjuvant to SRP significantly alleviated periodontal inflammation and tissue destruction compared to SRP alone. TISH(GR) treatment was associated with decreased TH17 cell infiltration and elevated expression of the Tregs-associated cytokine IL-10 in the periodontium. In conclusion, TISH(GR) was developed and optimized as an injectable immunomodulatory hydrogel targeting DCs and T-cells. It demonstrated promising potential to attenuate inflammation and enhance periodontal healing, particularly in immunocompromised patients with metabolic syndrome. STATEMENT OF SIGNIFICANCE: Current treatments for periodontitis primarily focus on dental plaque removal, with healing heavily dependent on the host immune system. However, metabolic diseases can dysregulate the local immune response, exacerbating periodontal inflammation and impairing post-treatment healing. In this study, we developed a chitosan-based hydrogel designed to immunomodulate dendritic cells and T-cells, polarizing them toward an anti-inflammatory phenotype that promotes tissue repair. When administered as an adjuvant to scaling and root planing, this combination therapy significantly enhanced periodontal healing and reduced tissue damage in a high-fat diet complicated periodontitis model. These findings highlight the clinical potential of this hydrogel formulation to improve treatment outcomes, particularly in challenging clinical cases involving metabolic comorbidities.
Collapse
Affiliation(s)
- Yi Zhu
- Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON, M5G 1G6, Canada
| | - Aiman Ali
- Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON, M5G 1G6, Canada
| | - Gabriel Mulinari Dos Santos
- Department of Diagnostic and Surgery, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil
| | - João Paulo Soares Franciscon
- Department of Diagnostic and Surgery, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil
| | - Rafael Scaf de Molon
- Department of Diagnostic and Surgery, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil
| | - Cynthia Goh
- Department of Chemistry, University of Toronto, 80 George Street, Toronto, ON, M5S 3H6, Canada; Department of Materials Science and Engineering, University of Toronto, 84 College Street, Suite 140. Toronto, Ontario M5S 3E4 Canada
| | - Edilson Erovolino
- Department of Basic Science, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil
| | - Leticia Helena Theodoro
- Department of Diagnostic and Surgery, São Paulo State University (UNESP), School of Dentistry, Araçatuba, São Paulo, Brazil
| | - Annie Shrestha
- Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, ON, M5G 1G6, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
| |
Collapse
|
2
|
Brummer C, Singer K, Renner K, Bruss C, Hellerbrand C, Dorn C, Reichelt-Wurm S, Gronwald W, Pukrop T, Herr W, Banas M, Kreutz M. The spleen-liver axis supports obesity-induced systemic and fatty liver inflammation via MDSC and NKT cell enrichment. Mol Cell Endocrinol 2025; 601:112518. [PMID: 40054835 DOI: 10.1016/j.mce.2025.112518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 01/29/2025] [Accepted: 03/05/2025] [Indexed: 04/01/2025]
Abstract
Obesity promotes adipose tissue inflammation and leads to impaired local but also systemic immune cell homeostasis. This chronic low-grade inflammation plays a significant role in the development of obesity-associated secondary diseases such as metabolic associated fatty liver disease or cancer. The spleen as the central organ of immune cell regulation is anatomically directly connected to the visceral adipose tissue and the liver via the portal vein circulation. However, the inter-organ crosstalk and linkage between obesity-induced systemic, hepatic and splenic immune cell dysregulation is not clearly outlined. In this study blood, spleen, and liver immune cells of non-obese wildtype vs. leptin deficient obese BTBR mice were isolated and analyzed in terms of leukocyte composition by flow cytometry. Significant differences between circulating, spleen- and liver-resident immune cell distribution revealed, that obesity-induced hepatic and systemic immune cell dysregulation is distinct from splenic immune cell reprogramming. Fatty liver inflammation was associated with splenic myeloid derived suppressor cell (MDSC) and natural killer T cell (NKT) enrichment whereas loss of hepatic T and B cells was not reflected by the splenic lymphocyte landscape. Correlation analysis confirmed a selective strong positive correlation between spleen and liver MDSC and NKT cell distribution indicating that the spleen-liver axis modulates obesity-induced immune dysregulation in a cell-specific manner. Similar results were observed in a diet-induced obesity mouse model. These data provide novel insights into the role of the spleen-liver axis in obesity-induced inflammation and foster the understanding of obesity-associated complications such as fatty liver disease and cancer.
Collapse
Affiliation(s)
- Christina Brummer
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany.
| | - Katrin Singer
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Kathrin Renner
- Department of Otorhinolaryngology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Christina Bruss
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany; Department of Gynecology and Obstetrics, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Claus Hellerbrand
- Institute of Biochemistry, University of Erlangen, 91054, Erlangen, Germany
| | - Christoph Dorn
- Institute of Pharmacy, University of Regensburg, 93053, Regensburg, Germany
| | - Simone Reichelt-Wurm
- Department of Nephrology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Wolfram Gronwald
- Institute of Functional Genomics, University of Regensburg, 93053, Regensburg, Germany
| | - Tobias Pukrop
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany; Comprehensive Cancer Center Ostbayern (CCCO), 93053, Regensburg, Germany
| | - Wolfgang Herr
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Miriam Banas
- Department of Nephrology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Marina Kreutz
- Department of Internal Medicine III, University Hospital Regensburg, 93053, Regensburg, Germany
| |
Collapse
|
3
|
Kong Y, Yang H, Nie R, Zhang X, Zuo F, Zhang H, Nian X. Obesity: pathophysiology and therapeutic interventions. MOLECULAR BIOMEDICINE 2025; 6:25. [PMID: 40278960 PMCID: PMC12031720 DOI: 10.1186/s43556-025-00264-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 03/15/2025] [Accepted: 03/24/2025] [Indexed: 04/26/2025] Open
Abstract
Over the past few decades, obesity has transitioned from a localized health concern to a pressing global public health crisis affecting over 650 million adults globally, as documented by WHO epidemiological surveys. As a chronic metabolic disorder characterized by pathological adipose tissue expansion, chronic inflammation, and neuroendocrine dysregulation that disrupts systemic homeostasis and impairs physiological functions, obesity is rarely an isolated condition; rather, it is frequently complicated by severe comorbidities that collectively elevate mortality risks. Despite advances in nutritional science and public health initiatives, sustained weight management success rates and prevention in obesity remain limited, underscoring its recognition as a multifactorial disease influenced by genetic, environmental, and behavioral determinants. Notably, the escalating prevalence of obesity and its earlier onset in younger populations have intensified the urgency to develop novel therapeutic agents that simultaneously ensure efficacy and safety. This review aims to elucidate the pathophysiological mechanisms underlying obesity, analyze its major complications-including type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), non-alcoholic fatty liver disease (NAFLD), obesity-related respiratory disorders, obesity-related nephropathy (ORN), musculoskeletal impairments, malignancies, and psychological comorbidities-and critically evaluate current anti-obesity strategies. Particular emphasis is placed on emerging pharmacological interventions, exemplified by plant-derived natural compounds such as berberine (BBR), with a focus on their molecular mechanisms, clinical efficacy, and therapeutic advantages. By integrating mechanistic insights with clinical evidence, this review seeks to provide innovative perspectives for developing safe, accessible, and effective obesity treatments.
Collapse
Affiliation(s)
- Yue Kong
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | | | - Rong Nie
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xuxiang Zhang
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Fan Zuo
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | | | - Xin Nian
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
| |
Collapse
|
4
|
Li D, Zhu J, Zhang M, Shi Q, Guo R, Zhang D, Zheng P, Zhang H, Li G, Wu J, Sun G, Wen Q, Tan J, Liu Z, Liu X, Yang H, Lu H, Cao G, Yin Z, Wang Q. SOSTDC1 downregulation in CD4 + T cells confers protection against obesity-induced insulin resistance. Cell Rep 2025; 44:115496. [PMID: 40173040 DOI: 10.1016/j.celrep.2025.115496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 01/28/2025] [Accepted: 03/10/2025] [Indexed: 04/04/2025] Open
Abstract
Adipose-resident T cells play a crucial role in the development of obesity-induced insulin resistance. However, the specific mechanisms, particularly those involving non-immune cytokines, remain unclear. Here, we report significantly elevated levels of sclerostin domain-containing protein 1 (SOSTDC1) in individuals with type 2 diabetes (T2D), showing positive correlations with fasting glucose and HbA1c. T cell-specific Sostdc1-deficient mice exhibit resistance to age-induced adipose lipid accumulation and glucose dysregulation at 12 months and protect against obesity-induced insulin resistance without affecting proinflammatory macrophage infiltration or adipose inflammation. Mechanistically, SOSTDC1 disrupts the lipid balance in adipocytes by promoting lipogenesis and inhibiting lipolysis through the LRP5/6-β-catenin pathway. Furthermore, T cell receptor (TCR) signaling significantly amplifies SOSTDC1 secretion in CD4+ T cells. In summary, our study uncovers an additional mechanism by which T cells contribute to obesity and insulin resistance, suggesting that inhibiting SOSTDC1 could be a promising immunotherapeutic strategy for metabolic disorders.
Collapse
Affiliation(s)
- Dehai Li
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Jing Zhu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China
| | - Mingyue Zhang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China
| | - Qiping Shi
- Department of Endocrinology, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China
| | - Rong Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Daming Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China
| | - Pei Zheng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China
| | - Hua Zhang
- Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Guangqiang Li
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China
| | - Jie Wu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China
| | - Guodong Sun
- Department of Orthopedics, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan 517000, China
| | - Qiong Wen
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China
| | - Jingyi Tan
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China
| | - Zonghua Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China
| | - Xindong Liu
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hengwen Yang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China.
| | - Hongyun Lu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China.
| | - Guangchao Cao
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China.
| | - Zhinan Yin
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China.
| | - Qian Wang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China.
| |
Collapse
|
5
|
Domagalski M, Olszańska J, Pietraszek‐Gremplewicz K, Nowak D. The role of adipogenic niche resident cells in colorectal cancer progression in relation to obesity. Obes Rev 2025; 26:e13873. [PMID: 39763022 PMCID: PMC11884973 DOI: 10.1111/obr.13873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 10/03/2024] [Accepted: 11/05/2024] [Indexed: 03/08/2025]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide and has one of the highest mortality rates. Considering its nonlinear etiology, many risk factors are associated with CRC formation and development, with obesity at the forefront. Obesity is regarded as one of the key environmental risk determinants for the pathogenesis of CRC. Excessive food intake and a sedentary lifestyle, together with genetic predispositions, lead to the overgrowth of adipose tissue along with a disruption in the number and function of its building cells. Adipose tissue-resident cells may constitute part of the CRC microenvironment. Alterations in their physiology and secretory profiles observed in obesity may further contribute to CRC progression, and despite similar localization, their contributions are not equivalent. They can interact with CRC cells, either directly or indirectly, influencing various processes that contribute to tumorigenesis. The main aim of this review is to provide insights into the diversity of adipose tissue resident cells, namely, adipocytes, adipose stromal cells, and immunological cells, regarding the role of particular cell types in co-forming the CRC microenvironment. The scope of this study was also devoted to the abnormalities in adipose tissue physiology observed in obesity states and their impact on CRC development.
Collapse
Affiliation(s)
- Mikołaj Domagalski
- Department of Cell Pathology, Faculty of BiotechnologyUniversity of WroclawWroclawPoland
| | - Joanna Olszańska
- Department of Cell Pathology, Faculty of BiotechnologyUniversity of WroclawWroclawPoland
| | | | - Dorota Nowak
- Department of Cell Pathology, Faculty of BiotechnologyUniversity of WroclawWroclawPoland
| |
Collapse
|
6
|
Yang J, Yang L, Wang Y, Huai L, Shi B, Zhang D, Xu W, Cui D. Interleukin-6 related signaling pathways as the intersection between chronic diseases and sepsis. Mol Med 2025; 31:34. [PMID: 39891057 PMCID: PMC11783753 DOI: 10.1186/s10020-025-01089-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 01/16/2025] [Indexed: 02/03/2025] Open
Abstract
Sepsis is associated with immune dysregulated and organ dysfunction due to severe infection. Clinicians aim to restore organ function, rather than prevent diseases that are prone to sepsis, resulting in high mortality and a heavy public health burden. Some chronic diseases can induce sepsis through inflammation cascade reaction and Cytokine Storm (CS). Interleukin (IL)-6, the core of CS, and its related signaling pathways have been considered as contributors to sepsis. Therefore, it is important to study the relationship between IL-6 and its related pathways in sepsis-related chronic diseases. This review generalized the mechanism of sepsis-related chronic diseases via IL-6 related pathways with the purpose to take rational management for these diseases. IL-6 related signaling pathways were sought in Kyoto Encyclopedia of Genes and Genomes (KEGG), and retrieved protein-protein interaction in the Search for Interaction Genes tool (STRING). In PubMed and Google Scholar, the studies were searched out, which correlating to IL-6 related pathways and associating with the pathological process of sepsis. Focused on the interactions of sepsis and IL-6 related pathways, some chronic diseases have been studied for association with sepsis, containing insulin resistance, Alcoholic liver disease (ALD), Alzheimer disease (AD), and atherosclerosis. This article summarized the inflammatory mechanisms of IL-6 cross-talked with other mediators of some chronic diseases in vitro, animal models, and human experiments, leading to the activation of pathways and accelerating the progression of sepsis. The clinicians should be highlight to this kind of diseases and more clinical trials are needed to provide more reliable theoretical basis for health policy formulation.
Collapse
Affiliation(s)
- Jie Yang
- Department of Emergency, the People's Hospital of Liaoning Province, 33 Wenyi Road, Shenhe District, Shenyang, 110016, China.
| | - Lin Yang
- Department of Emergency, the People's Hospital of Liaoning Province, 33 Wenyi Road, Shenhe District, Shenyang, 110016, China
| | - Yanjiao Wang
- Department of Emergency, the People's Hospital of Liaoning Province, 33 Wenyi Road, Shenhe District, Shenyang, 110016, China
| | - Lu Huai
- Department of Emergency, the People's Hospital of Liaoning Province, 33 Wenyi Road, Shenhe District, Shenyang, 110016, China
| | - Bohan Shi
- Department of Emergency, the People's Hospital of Liaoning Province, 33 Wenyi Road, Shenhe District, Shenyang, 110016, China
| | - Di Zhang
- Department of Emergency, the People's Hospital of Liaoning Province, 33 Wenyi Road, Shenhe District, Shenyang, 110016, China
| | - Wei Xu
- Department of Emergency, the People's Hospital of Liaoning Province, 33 Wenyi Road, Shenhe District, Shenyang, 110016, China
| | - Di Cui
- Department of Emergency, the People's Hospital of Liaoning Province, 33 Wenyi Road, Shenhe District, Shenyang, 110016, China
| |
Collapse
|
7
|
Zhang Q, Yang Z, Ou X, Zhang M, Qin X, Wu G. The role of immunity in insulin resistance in patients with polycystic ovary syndrome. Front Endocrinol (Lausanne) 2025; 15:1464561. [PMID: 39911236 PMCID: PMC11797073 DOI: 10.3389/fendo.2024.1464561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 12/31/2024] [Indexed: 02/07/2025] Open
Abstract
Polycystic ovary syndrome (PCOS) is a prevalent disorder of the endocrine system with significant clinical implications, often leading to health complications related to adipose tissue accumulation, including obesity, insulin resistance (IR), metabolic syndrome, and type 2 diabetes mellitus. While the precise pathogenesis of PCOS remains unclear, it is now recognized that genetic, endocrine, and metabolic dysregulations all contribute significantly to its onset. The immunopathogenesis of PCOS has not been extensively explored, but there is growing speculation that immune system abnormalities may play a pivotal role. This chronic inflammatory state is exacerbated by factors such as obesity and hyperinsulinemia. Therefore, this review aims to elucidate the interplay between IR in PCOS patients, the controlled immune response orchestrated by immune cells and immunomodulatory molecules, and their interactions with adipocytes, hyperandrogenemia, chronic inflammation, and metabolic homeostasis.
Collapse
Affiliation(s)
- Qixuan Zhang
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhe Yang
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiangyang Ou
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mengying Zhang
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiangyu Qin
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Gengxiang Wu
- Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, China
| |
Collapse
|
8
|
Panichi V, Costantini S, Grasso M, Arciola CR, Dolzani P. Innate Immunity and Synovitis: Key Players in Osteoarthritis Progression. Int J Mol Sci 2024; 25:12082. [PMID: 39596150 PMCID: PMC11594236 DOI: 10.3390/ijms252212082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
Osteoarthritis (OA) is a chronic progressive disease of the joint. Although representing the most frequent cause of disability in the elderly, OA remains partly obscure in its pathogenic mechanisms and is still the orphan of resolutive therapies. The concept of what was once considered a "wear and tear" of articular cartilage is now that of an inflammation-related disease that affects over time the whole joint. The attention is increasingly focused on the synovium. Even from the earliest clinical stages, synovial inflammation (or synovitis) is a crucial factor involved in OA progression and a major player in pain onset. The release of inflammatory molecules in the synovium mediates disease progression and worsening of clinical features. The activation of synovial tissue-resident cells recalls innate immunity cells from the bloodstream, creating a proinflammatory milieu that fuels and maintains a damaging condition of low-grade inflammation in the joint. In such a context, cellular and molecular inflammatory behaviors in the synovium could be the primum movens of the structural and functional alterations of the whole joint. This paper focuses on and discusses the involvement of innate immunity cells in synovitis and their role in the progression of OA.
Collapse
Affiliation(s)
- Veronica Panichi
- Laboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Silvia Costantini
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40136 Bologna, Italy; (S.C.); (M.G.)
| | - Merimma Grasso
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40136 Bologna, Italy; (S.C.); (M.G.)
| | - Carla Renata Arciola
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40136 Bologna, Italy; (S.C.); (M.G.)
- Laboratory of Immunorheumatology and Tissue Regeneration, Laboratory of Pathology of Implant Infections, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Paolo Dolzani
- Laboratory of Immunorheumatology and Tissue Regeneration, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| |
Collapse
|
9
|
Connolly BJ, Saxton SN. Recent updates on the influence of iron and magnesium on vascular, renal, and adipose inflammation and possible consequences for hypertension. J Hypertens 2024; 42:1848-1861. [PMID: 39258532 PMCID: PMC11451934 DOI: 10.1097/hjh.0000000000003829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 06/26/2024] [Accepted: 07/22/2024] [Indexed: 09/12/2024]
Abstract
The inflammatory status of the kidneys, vasculature, and perivascular adipose tissue (PVAT) has a significant influence on blood pressure and hypertension. Numerous micronutrients play an influential role in hypertension-driving inflammatory processes, and recent reports have provided bases for potential targeted modulation of these micronutrients to reduce hypertension. Iron overload in adipose tissue macrophages and adipocytes engenders an inflammatory environment and may contribute to impaired anticontractile signalling, and thus a treatment such as chelation therapy may hold a key to reducing blood pressure. Similarly, magnesium intake has proven to greatly influence inflammatory signalling and concurrent hypertension in both healthy animals and in a model for chronic kidney disease, demonstrating its potential clinical utility. These findings highlight the importance of further research to determine the efficacy of micronutrient-targeted treatments for the amelioration of hypertension and their potential translation into clinical application.
Collapse
Affiliation(s)
- Benjamin J Connolly
- Divison of Cardiovascular Sciences, The University of Manchester, Manchester, UK
| | | |
Collapse
|
10
|
Turner MB, Dalmasso C, Loria AS. The adipose tissue keeps the score: priming of the adrenal-adipose tissue axis by early life stress predisposes women to obesity and cardiometabolic risk. Front Endocrinol (Lausanne) 2024; 15:1481923. [PMID: 39493777 PMCID: PMC11527639 DOI: 10.3389/fendo.2024.1481923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 09/26/2024] [Indexed: 11/05/2024] Open
Abstract
Adverse Childhood Experiences (ACEs) refer to early life stress events, including abuse, neglect, and other psychosocial childhood traumas that can have long-lasting effects on a wide range of physiological functions. ACEs provoke sex-specific effects, whereas women have been shown to display a strong positive correlation with obesity and cardiometabolic disease. Notably, rodent models of chronic behavioral stress during postnatal life recapitulate several effects of ACEs in a sex-specific fashion. In this review, we will discuss the potential mechanisms uncovered by models of early life stress that may explain the greater susceptibility of females to obesity and metabolic risk compared with their male counterparts. We highlight the early life stress-induced neuroendocrine shaping of the adrenal-adipose tissue axis as a primary event conferring sex-dependent heightened sensitivity to obesity.
Collapse
Affiliation(s)
| | | | - Analia S. Loria
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, United States
| |
Collapse
|
11
|
Soedono S, Julietta V, Nawaz H, Cho KW. Dynamic Roles and Expanding Diversity of Adipose Tissue Macrophages in Obesity. J Obes Metab Syndr 2024; 33:193-212. [PMID: 39324219 PMCID: PMC11443328 DOI: 10.7570/jomes24030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 09/21/2024] [Accepted: 09/24/2024] [Indexed: 09/27/2024] Open
Abstract
Adipose tissue macrophages (ATMs) are key regulators of adipose tissue (AT) inflammation and insulin resistance in obesity, and the traditional M1/M2 characterization of ATMs is inadequate for capturing their diversity in obese conditions. Single-cell transcriptomic profiling has revealed heterogeneity among ATMs that goes beyond the old paradigm and identified new subsets with unique functions. Furthermore, explorations of their developmental origins suggest that multiple differentiation pathways contribute to ATM variety. These advances raise concerns about how to define ATM functions, how they are regulated, and how they orchestrate changes in AT. This review provides an overview of the current understanding of ATMs and their updated categorization in both mice and humans during obesity. Additionally, diverse ATM functions and contributions in the context of obesity are discussed. Finally, potential strategies for targeting ATM functions as therapeutic interventions for obesity-induced metabolic diseases are addressed.
Collapse
Affiliation(s)
- Shindy Soedono
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Vivi Julietta
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Hadia Nawaz
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| | - Kae Won Cho
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea
| |
Collapse
|
12
|
Gallo G, Desideri G, Savoia C. Update on Obesity and Cardiovascular Risk: From Pathophysiology to Clinical Management. Nutrients 2024; 16:2781. [PMID: 39203917 PMCID: PMC11356794 DOI: 10.3390/nu16162781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 08/14/2024] [Accepted: 08/19/2024] [Indexed: 09/03/2024] Open
Abstract
Obesity is an epidemic worldwide. Overweight and multiple obesity-related mechanisms, including dysmetabolic alterations, contribute to cardiovascular deleterious effects. Hence, overweight and obesity have been independently associated with increased cardiovascular risk, whose assessment is crucial for preserving life quality and reducing mortality, and to address appropriate therapeutic strategies in obese patients. Beyond the standard of care in managing overweight and obesity in adults (i.e., diet and physical exercise), several relevant pharmacotherapies have been approved, and several procedures and device types for weight loss have been recommended. In such a contest, medical weight management remains one option for treating excess weight. Most drugs used for obesity reduce appetite and increase satiety and, secondarily, slow gastric emptying to reduce body weight and, therefore, act also to improve metabolic parameters. In this contest, agonists of the glucagon-like peptide-1 receptor (GLP-1RAs) modulate different metabolic pathways associated with glucose metabolism, energy homeostasis, antioxidation, and inflammation. Moreover, this class of drugs has shown efficacy in improving glycemic control, reducing the incidence of cardiovascular events in type 2 diabetic patients, and reducing body weight independently of the presence of diabetes. Recently, in overweight or obese patients with pre-existing cardiovascular disease but without diabetes, the GLP-1RA semaglutide reduced the incidence of cardiovascular and cerebrovascular events and death from cardiovascular causes. Thus, semaglutide has been approved for secondary prevention in obese people with cardiovascular disease. Nevertheless, whether this class of drugs is equally effective for primary prevention in obese people has to be demonstrated. In this review, we will summarize updates on the pathophysiology of obesity, the effects of obesity on cardiovascular risk, the impact of different obesity phenotypes on cardiovascular diseases, and the novelties in the clinical management of obesity for cardiovascular prevention.
Collapse
Affiliation(s)
- Giovanna Gallo
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy;
| | - Giovambattista Desideri
- Department of Clinical, Internal Medicine, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy;
| | - Carmine Savoia
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy;
| |
Collapse
|
13
|
Yang X, Tang H, Sun X, Gui Q. M6A modification and T cells in adipose tissue inflammation. Cell Biochem Funct 2024; 42:e4089. [PMID: 38978329 DOI: 10.1002/cbf.4089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 05/11/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024]
Abstract
Adipose tissue in the obese state can lead to low-grade chronic inflammation while inducing or exacerbating obesity-related metabolic diseases and impairing overall health.T cells, which are essential immune cells similar to macrophages, are widely distributed in adipose tissue and perform their immunomodulatory function; they also cross-talk with other cells in the vascular stromal fraction. Based on a large number of studies, it has been found that N6 methyl adenine (m6A) is one of the most representative of epigenetic modifications, which affects the crosstalk between T cells, as well as other immune cells, in several ways and plays an important role in the development of adipose tissue inflammation and related metabolic diseases. In this review, we first provide an overview of the widespread presence of T cells in adipose tissue and summarize the key role of T cells in adipose tissue inflammation. Next, we explored the effects of m6A modifications on T cells in adipose tissue from the perspective of adipose tissue inflammation. Finally, we discuss the impact of m6a-regulated crosstalk between T cells and immune cells on the prospects for improving adipose tissue inflammation research, providing additional new ideas for the treatment of obesity.
Collapse
Affiliation(s)
- Xiaoting Yang
- Institute of Translational Medicine, Department of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, China
| | - Haojun Tang
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, China
| | - Xuan Sun
- Institute of Translational Medicine, Department of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, China
| | - Qingjun Gui
- Institute of Translational Medicine, Department of Basic Medicine, Hengyang Medical School, University of South China, Hengyang, China
| |
Collapse
|
14
|
Valentine Y, Nikolajczyk BS. T cells in obesity-associated inflammation: The devil is in the details. Immunol Rev 2024; 324:25-41. [PMID: 38767210 PMCID: PMC11694249 DOI: 10.1111/imr.13354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Obesity presents a significant health challenge, affecting 41% of adults and 19.7% of children in the United States. One of the associated health challenges of obesity is chronic low-grade inflammation. In both mice and humans, T cells in circulation and in the adipose tissue play a pivotal role in obesity-associated inflammation. Changes in the numbers and frequency of specific CD4+ Th subsets and their contribution to inflammation through cytokine production indicate declining metabolic health, that is, insulin resistance and T2D. While some Th subset alterations are consistent between mice and humans with obesity, some changes mainly characterize male mice, whereas female mice often resist obesity and inflammation. However, protection from obesity and inflammation is not observed in human females, who can develop obesity-related T-cell inflammation akin to males. The decline in female sex hormones after menopause is also implicated in promoting obesity and inflammation. Age is a second underappreciated factor for defining and regulating obesity-associated inflammation toward translating basic science findings to the clinic. Weight loss in mice and humans, in parallel with these other factors, does not resolve obesity-associated inflammation. Instead, inflammation persists amid modest changes in CD4+ T cell frequencies, highlighting the need for further research into resolving changes in T-cell function after weight loss. How lingering inflammation after weight loss affecting the common struggle to maintain lower weight is unknown. Semaglutide, a newly popular pharmaceutical used for treating T2D and reversing obesity, holds promise for alleviating obesity-associated health complications, yet its impact on T-cell-mediated inflammation remains unexplored. Further work in this area could significantly contribute to the scientific understanding of the impacts of weight loss and sex/hormones in obesity and obesity-associated metabolic decline.
Collapse
Affiliation(s)
- Yolander Valentine
- Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, Kentucky, USA
| | - Barbara S. Nikolajczyk
- Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, Kentucky, USA
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky, USA
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky, USA
- Barnstable Brown Diabetes and Obesity Research Center, University of Kentucky, Lexington, Kentucky, USA
| |
Collapse
|
15
|
Gélineau A, Marcelin G, Ouhachi M, Dussaud S, Voland L, Manuel R, Baba I, Rouault C, Yvan-Charvet L, Clément K, Tussiwand R, Huby T, Gautier EL. Fructooligosaccharides benefits on glucose homeostasis upon high-fat diet feeding require type 2 conventional dendritic cells. Nat Commun 2024; 15:5413. [PMID: 38926424 PMCID: PMC11208547 DOI: 10.1038/s41467-024-49820-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 06/17/2024] [Indexed: 06/28/2024] Open
Abstract
Diet composition impacts metabolic health and is now recognized to shape the immune system, especially in the intestinal tract. Nutritional imbalance and increased caloric intake are induced by high-fat diet (HFD) in which lipids are enriched at the expense of dietary fibers. Such nutritional challenge alters glucose homeostasis as well as intestinal immunity. Here, we observed that short-term HFD induced dysbiosis, glucose intolerance and decreased intestinal RORγt+ CD4 T cells, including peripherally-induced Tregs and IL17-producing (Th17) T cells. However, supplementation of HFD-fed male mice with the fermentable dietary fiber fructooligosaccharides (FOS) was sufficient to maintain RORγt+ CD4 T cell subsets and microbial species known to induce them, alongside having a beneficial impact on glucose tolerance. FOS-mediated normalization of Th17 cells and amelioration of glucose handling required the cDC2 dendritic cell subset in HFD-fed animals, while IL-17 neutralization limited FOS impact on glucose tolerance. Overall, we uncover a pivotal role of cDC2 in the control of the immune and metabolic effects of FOS in the context of HFD feeding.
Collapse
Affiliation(s)
- Adélaïde Gélineau
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Geneviève Marcelin
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Nutrition and Obesities: Systemic approaches research group, NutriOmics, Paris, France
| | - Melissa Ouhachi
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Sébastien Dussaud
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Lise Voland
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Nutrition and Obesities: Systemic approaches research group, NutriOmics, Paris, France
| | - Raoul Manuel
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Ines Baba
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Christine Rouault
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Nutrition and Obesities: Systemic approaches research group, NutriOmics, Paris, France
| | - Laurent Yvan-Charvet
- Institut National de la Santé et de la Recherche Médicale, Inserm, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Nice, France
| | - Karine Clément
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Nutrition and Obesities: Systemic approaches research group, NutriOmics, Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, service de Nutrition, Paris, France
| | - Roxane Tussiwand
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Thierry Huby
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Emmanuel L Gautier
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France.
| |
Collapse
|
16
|
Yang Z, Chen F, Zhang Y, Ou M, Tan P, Xu X, Li Q, Zhou S. Therapeutic targeting of white adipose tissue metabolic dysfunction in obesity: mechanisms and opportunities. MedComm (Beijing) 2024; 5:e560. [PMID: 38812572 PMCID: PMC11134193 DOI: 10.1002/mco2.560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 04/09/2024] [Accepted: 04/14/2024] [Indexed: 05/31/2024] Open
Abstract
White adipose tissue is not only a highly heterogeneous organ containing various cells, such as adipocytes, adipose stem and progenitor cells, and immune cells, but also an endocrine organ that is highly important for regulating metabolic and immune homeostasis. In individuals with obesity, dynamic cellular changes in adipose tissue result in phenotypic switching and adipose tissue dysfunction, including pathological expansion, WAT fibrosis, immune cell infiltration, endoplasmic reticulum stress, and ectopic lipid accumulation, ultimately leading to chronic low-grade inflammation and insulin resistance. Recently, many distinct subpopulations of adipose tissue have been identified, providing new insights into the potential mechanisms of adipose dysfunction in individuals with obesity. Therefore, targeting white adipose tissue as a therapeutic agent for treating obesity and obesity-related metabolic diseases is of great scientific interest. Here, we provide an overview of white adipose tissue remodeling in individuals with obesity including cellular changes and discuss the underlying regulatory mechanisms of white adipose tissue metabolic dysfunction. Currently, various studies have uncovered promising targets and strategies for obesity treatment. We also outline the potential therapeutic signaling pathways of targeting adipose tissue and summarize existing therapeutic strategies for antiobesity treatment including pharmacological approaches, lifestyle interventions, and novel therapies.
Collapse
Affiliation(s)
- Zi‐Han Yang
- Department of Plastic and Burn SurgeryWest China Hospital of Sichuan UniversityChengduChina
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Fang‐Zhou Chen
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yi‐Xiang Zhang
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Min‐Yi Ou
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Poh‐Ching Tan
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xue‐Wen Xu
- Department of Plastic and Burn SurgeryWest China Hospital of Sichuan UniversityChengduChina
| | - Qing‐Feng Li
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shuang‐Bai Zhou
- Department of Plastic & Reconstructive SurgeryShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| |
Collapse
|
17
|
Su Z, Sun JY, Gao M, Sun W, Kong X. Molecular mechanisms and potential therapeutic targets in the pathogenesis of hypertension in visceral adipose tissue induced by a high-fat diet. Front Cardiovasc Med 2024; 11:1380906. [PMID: 38689862 PMCID: PMC11058983 DOI: 10.3389/fcvm.2024.1380906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 04/04/2024] [Indexed: 05/02/2024] Open
Abstract
Background Hypertension (HTN) presents a significant global public health challenge with diverse causative factors. The accumulation of visceral adipose tissue (VAT) due to a high-fat diet (HFD) is an independent risk factor for HTN. While various studies have explored pathogenic mechanisms, a comprehensive understanding of impact of VAT on blood pressure necessitates bioinformatics analysis. Methods Datasets GSE214618 and GSE188336 were acquired from the Gene Expression Omnibus and analyzed to identify shared differentially expressed genes between HFD-VAT and HTN-VAT. Gene Ontology enrichment and protein-protein interaction analyses were conducted, leading to the identification of hub genes. We performed molecular validation of hub genes using RT-qPCR, Western-blotting and immunofluorescence staining. Furthermore, immune infiltration analysis using CIBERSORTx was performed. Results This study indicated that the predominant characteristic of VAT in HTN was related to energy metabolism. The red functional module was enriched in pathways associated with mitochondrial oxidative respiration and ATP metabolism processes. Spp1, Postn, and Gpnmb in VAT were identified as hub genes on the pathogenic mechanism of HTN. Proteins encoded by these hub genes were closely associated with the target organs-specifically, the resistance artery, aorta, and heart tissue. After treatment with empagliflozin, there was a tendency for Spp1, Postn, and Gpnmb to decrease in VAT. Immune infiltration analysis confirmed that inflammation and immune response may not be the main mechanisms by which visceral adiposity contributes to HTN. Conclusions Our study pinpointed the crucial causative factor of HTN in VAT following HFD. Spp1, Postn, and Gpnmb in VAT acted as hub genes that promote elevated blood pressure and can be targets for HTN treatment. These findings contributed to therapeutic strategies and prognostic markers for HTN.
Collapse
Affiliation(s)
- Zhenyang Su
- School of Medicine, Southeast University, Nanjing, China
| | - Jin-Yu Sun
- Department of Cardiology, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
| | - Min Gao
- Department of Cardiology, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
| | - Wei Sun
- Department of Cardiology, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
| | - Xiangqing Kong
- School of Medicine, Southeast University, Nanjing, China
- Department of Cardiology, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
| |
Collapse
|
18
|
Rose S, Landes RD, Vyas KK, Delhey L, Blossom S. Regulatory T cells and bioenergetics of peripheral blood mononuclear cells linked to pediatric obesity. IMMUNOMETABOLISM (COBHAM, SURREY) 2024; 6:e00040. [PMID: 38680993 PMCID: PMC11045398 DOI: 10.1097/in9.0000000000000040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/14/2024] [Indexed: 05/01/2024]
Abstract
Background Obesity-associated inflammation drives the development of insulin resistance and type 2 diabetes. We sought to identify associations of circulating regulatory T cells (Treg) with the degree of obesity (eg, body mass index Z-score [BMIz]), insulin resistance (homeostatic model of insulin resistance [HOMA-IR]), and glycemic control (HbA1c) in children and adolescents. We further sought to examine associations among bioenergetics of peripheral blood mononuclear cells (PBMCs) and CD4 T cells and BMIz, HOMA-IR, and HbA1c. Methods A total of 65 children and adolescents between the ages 5 and 17 years were studied. HbA1c and fasting levels of plasma glucose and insulin were measured. We quantified circulating Tregs (CD3+CD4+CD25+CD127-FoxP3+) by flow cytometry, and measured mitochondrial respiration (oxygen consumption rate [OCR]) and glycolysis (extracellular acidification rate [ECAR]) in PBMCs and isolated CD4 T cells by Seahorse extracellular flux analysis. Results Tregs (% CD4) are negatively associated with BMIz but positively associated with HOMA-IR. In PBMCs, OCR/ECAR (a ratio of mitochondrial respiration to glycolysis) is positively associated with BMIz but negatively associated with HbA1c. Conclusions In children, Tregs decrease as body mass index increases; however, the metabolic stress and inflammation associated with insulin resistance may induce a compensatory increase in Tregs. The degree of obesity is also associated with a shift away from glycolysis in PBMCs but as HbA1c declines, metabolism shifts back toward glycolysis. Comprehensive metabolic assessment of the immune system is needed to better understand the implications immune cell metabolic alterations in the progression from a healthy insulin-sensitive state toward glucose intolerance in children. Trial registration This observational study was registered at the ClinicalTrials.gov (NCT03960333, https://clinicaltrials.gov/study/NCT03960333?term=NCT03960333&rank=1).
Collapse
Affiliation(s)
- Shannon Rose
- Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Arkansas Children’s Research Institute, Little Rock, AR, USA
| | - Reid D. Landes
- Department of Biostatistics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Kanan K. Vyas
- Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Arkansas Children’s Research Institute, Little Rock, AR, USA
| | - Leanna Delhey
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Sarah Blossom
- Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM, USA
| |
Collapse
|
19
|
Soedono S, Sharlene S, Vo DHN, Averia M, Rosalie EE, Lee YK, Cho KW. Obese visceral adipose dendritic cells downregulate regulatory T cell development through IL-33. Front Immunol 2024; 15:1335651. [PMID: 38566998 PMCID: PMC10985834 DOI: 10.3389/fimmu.2024.1335651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/08/2024] [Indexed: 04/04/2024] Open
Abstract
Regulatory T cells (Tregs) residing in visceral adipose tissue (VAT) play a pivotal role in regulating tissue inflammation and metabolic dysfunction associated with obesity. However, the specific phenotypic and functional characteristics of Tregs in obese VAT, as well as the regulatory mechanisms shaping them, remain elusive. This study demonstrates that obesity selectively reduces Tregs in VAT, characterized by restrained proliferation, heightened PD-1 expression, and diminished ST2 expression. Additionally, obese VAT displays distinctive maturation of dendritic cells (DCs), marked by elevated expressions of MHC-II, CD86, and PD-L1, which are inversely correlated with VAT Tregs. In an in vitro co-culture experiment, only obese VAT DCs, not macrophages or DCs from subcutaneous adipose tissue (SAT) and spleen, result in decreased Treg differentiation and proliferation. Furthermore, Tregs differentiated by obese VAT DCs exhibit distinct characteristics resembling those of Tregs in obese VAT, such as reduced ST2 and IL-10 expression. Mechanistically, obesity lowers IL-33 production in VAT DCs, contributing to the diminished Treg differentiation. These findings collectively underscore the critical role of VAT DCs in modulating Treg generation and shaping Treg phenotype and function during obesity, potentially contributing to the regulation of VAT Treg populations.
Collapse
Affiliation(s)
- Shindy Soedono
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Republic of Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Republic of Korea
| | - Sharlene Sharlene
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Republic of Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Republic of Korea
| | - Dan Hoang Nguyet Vo
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Republic of Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Republic of Korea
| | - Maria Averia
- Magister of Biotechnology, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
| | - Eufrasia Elaine Rosalie
- Faculty of Biotechnology, Department of Food Technology, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia
| | - Yun Kyung Lee
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Republic of Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Republic of Korea
| | - Kae Won Cho
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan, Republic of Korea
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Republic of Korea
| |
Collapse
|
20
|
Nicholas DA, Mbongue JC, Garcia-Pérez D, Sorensen D, Ferguson Bennit H, De Leon M, Langridge WHR. Exploring the Interplay between Fatty Acids, Inflammation, and Type 2 Diabetes. IMMUNO 2024; 4:91-107. [PMID: 39606781 PMCID: PMC11600342 DOI: 10.3390/immuno4010006] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024] Open
Abstract
Around 285 million people worldwide currently have type 2 diabetes and it is projected that this number will be surpassed by 2030. Therefore, it is of the utmost importance to enhance our comprehension of the disease's development. The regulation of diet, obesity, and inflammation in type 2 diabetes is believed to play a crucial role in enhancing insulin sensitivity and reducing the risk of onset diabetes. Obesity leads to an increase in visceral adipose tissue, which is a prominent site of inflammation in type 2 diabetes. Dyslipidemia, on the other hand, plays a significant role in attracting activated immune cells such as macrophages, dendritic cells, T cells, NK cells, and B cells to visceral adipose tissue. These immune cells are a primary source of pro-inflammatory cytokines that are believed to promote insulin resistance. This review delves into the influence of elevated dietary free saturated fatty acids and examines the cellular and molecular factors associated with insulin resistance in the initiation of inflammation induced by obesity. Furthermore, it explores novel concepts related to diet-induced inflammation and its relationship with type 2 diabetes.
Collapse
Affiliation(s)
- Dequina A. Nicholas
- School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA
| | - Jacques C. Mbongue
- Department of Biological Sciences, School of Arts and Sciences, Oakwood University, Huntsville, AL 35896, USA
| | - Darysbel Garcia-Pérez
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
- Division of Molecular Genetics and Microbiology, School of Medicine Alumni Hall, Loma Linda University, Rm 102, 11021 Campus Street, Loma Linda, CA 92350, USA
| | - Dane Sorensen
- Center for Perinatal Biology, Division of Physiology, Loma Linda School of Medicine, Rm A572, 11234 Anderson Street, Loma Linda, CA 92350, USA
| | - Heather Ferguson Bennit
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
| | - Marino De Leon
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
| | - William H. R. Langridge
- Center for Health Disparities and Molecular Medicine, School of Medicine, Loma Linda University, Loma Linda, CA 11085, USA
| |
Collapse
|
21
|
Susca N, Leone P, Prete M, Cozzio S, Racanelli V. Adipose failure through adipocyte overload and autoimmunity. Autoimmun Rev 2024; 23:103502. [PMID: 38101692 DOI: 10.1016/j.autrev.2023.103502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 12/10/2023] [Indexed: 12/17/2023]
Abstract
Metabolic syndrome poses a great worldwide threat to the health of the patients. Increased visceral adiposity is recognized as the main determinant of the detrimental clinical effects of insulin resistance. Inflammation and immune system activation in the adipose tissue (AT) have a central role in the pathophysiology of metabolic syndrome, but the mechanisms linking increased adiposity to immunity in the AT remain in part elusive. In this review, we support the central role of adipocyte overload and relative adipose failure as key determinants in triggering immune aggression to AT. This provides a mechanistic explanation of the relative metabolic wellness of metabolically normal obese people and the disruption in insulin signaling in metabolically obese lean people.
Collapse
Affiliation(s)
- Nicola Susca
- Department of Interdisciplinary Medicine, School of Medicine, 'Aldo Moro' University of Bari, 70124 Bari, Italy
| | - Patrizia Leone
- Department of Interdisciplinary Medicine, School of Medicine, 'Aldo Moro' University of Bari, 70124 Bari, Italy
| | - Marcella Prete
- Department of Interdisciplinary Medicine, School of Medicine, 'Aldo Moro' University of Bari, 70124 Bari, Italy
| | - Susanna Cozzio
- U.O. di Medicina Interna, Ospedale di Rovereto, Azienda Sanitaria per i Servizi Provinciali di Trento, Trento, Italy
| | - Vito Racanelli
- Centre for Medical Sciences - CISMed, University of Trento and Department of Internal Medicine, Santa Chiara Hospital, Trento, Italy.
| |
Collapse
|
22
|
Bradley D, Deng T, Shantaram D, Hsueh WA. Orchestration of the Adipose Tissue Immune Landscape by Adipocytes. Annu Rev Physiol 2024; 86:199-223. [PMID: 38345903 DOI: 10.1146/annurev-physiol-042222-024353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2024]
Abstract
Obesity is epidemic and of great concern because of its comorbid and costly inflammatory-driven complications. Extensive investigations in mice have elucidated highly coordinated, well-balanced interactions between adipocytes and immune cells in adipose tissue that maintain normal systemic metabolism in the lean state, while in obesity, proinflammatory changes occur in nearly all adipose tissue immune cells. Many of these changes are instigated by adipocytes. However, less is known about obesity-induced adipose-tissue immune cell alterations in humans. Upon high-fat diet feeding, the adipocyte changes its well-known function as a metabolic cell to assume the role of an immune cell, orchestrating proinflammatory changes that escalate inflammation and progress during obesity. This transformation is particularly prominent in humans. In this review, we (a) highlight a leading and early role for adipocytes in promulgating inflammation, (b) discuss immune cell changes and the time course of these changes (comparing humans and mice when possible), and (c) note how reversing proinflammatory changes in most types of immune cells, including adipocytes, rescues adipose tissue from inflammation and obese mice from insulin resistance.
Collapse
Affiliation(s)
- David Bradley
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA;
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Pennsylvania State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA;
| | - Tuo Deng
- Second Xiangya Hospital, Central South University, Changsha, China
| | - Dharti Shantaram
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA;
| | - Willa A Hsueh
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA;
| |
Collapse
|
23
|
Ren W, Hua M, Cao F, Zeng W. The Sympathetic-Immune Milieu in Metabolic Health and Diseases: Insights from Pancreas, Liver, Intestine, and Adipose Tissues. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306128. [PMID: 38039489 PMCID: PMC10885671 DOI: 10.1002/advs.202306128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/28/2023] [Indexed: 12/03/2023]
Abstract
Sympathetic innervation plays a crucial role in maintaining energy balance and contributes to metabolic pathophysiology. Recent evidence has begun to uncover the innervation landscape of sympathetic projections and sheds light on their important functions in metabolic activities. Additionally, the immune system has long been studied for its essential roles in metabolic health and diseases. In this review, the aim is to provide an overview of the current research progress on the sympathetic regulation of key metabolic organs, including the pancreas, liver, intestine, and adipose tissues. In particular, efforts are made to highlight the critical roles of the peripheral nervous system and its potential interplay with immune components. Overall, it is hoped to underscore the importance of studying metabolic organs from a comprehensive and interconnected perspective, which will provide valuable insights into the complex mechanisms underlying metabolic regulation and may lead to novel therapeutic strategies for metabolic diseases.
Collapse
Affiliation(s)
- Wenran Ren
- Institute for Immunology and School of MedicineTsinghua Universityand Tsinghua‐Peking Center for Life SciencesBeijing100084China
| | - Meng Hua
- Institute for Immunology and School of MedicineTsinghua Universityand Tsinghua‐Peking Center for Life SciencesBeijing100084China
| | - Fang Cao
- Department of NeurosurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhou563000China
| | - Wenwen Zeng
- Institute for Immunology and School of MedicineTsinghua Universityand Tsinghua‐Peking Center for Life SciencesBeijing100084China
- SXMU‐Tsinghua Collaborative Innovation Center for Frontier MedicineTaiyuan030001China
- Beijing Key Laboratory for Immunological Research on Chronic DiseasesBeijing100084China
| |
Collapse
|
24
|
Engin A. Reappraisal of Adipose Tissue Inflammation in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:297-327. [PMID: 39287856 DOI: 10.1007/978-3-031-63657-8_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Chronic low-grade inflammation is a central component in the pathogenesis of obesity-related expansion of adipose tissue and complications in other metabolic tissues. Five different signaling pathways are defined as dominant determinants of adipose tissue inflammation: These are increased circulating endotoxin due to dysregulation in the microbiota-gut-brain axis, systemic oxidative stress, macrophage accumulation, and adipocyte death. Finally, the nucleotide-binding and oligomerization domain (NOD) leucine-rich repeat family pyrin domain-containing 3 (NLRP3) inflammasome pathway is noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome and associated metabolic inflammation play an important role in the relationships among fatty acids and obesity. Several highly active molecules, including primarily leptin, resistin, adiponectin, visfatin, and classical cytokines, are abundantly released from adipocytes. The most important cytokines that are released by inflammatory cells infiltrating obese adipose tissue are tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2), and IL-1. All these molecules mentioned above act on immune cells, causing local and then general inflammation. Three metabolic pathways are noteworthy in the development of adipose tissue inflammation: toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, endoplasmic reticulum (ER) stress-derived unfolded protein response (UPR), and inhibitor of nuclear factor kappa-B kinase beta (IKKβ)-nuclear factor kappa B (NF-κB) pathway. In fact, adipose tissue inflammation is an adaptive response that contributes to a visceral depot barrier that effectively filters gut-derived endotoxin. Excessive fatty acid release worsens adipose tissue inflammation and contributes to insulin resistance. However, suppression of adipose inflammation in obesity with anti-inflammatory drugs is not a rational solution and paradoxically promotes insulin resistance, despite beneficial effects on weight gain. Inflammatory pathways in adipocytes are indeed indispensable for maintaining systemic insulin sensitivity. Cannabinoid type 1 receptor (CB1R) is important in obesity-induced pro-inflammatory response; however, blockade of CB1R, contrary to anti-inflammatory drugs, breaks the links between insulin resistance and adipose tissue inflammation. Obesity, however, could be decreased by improving leptin signaling, white adipose tissue browning, gut microbiota interactions, and alleviating inflammation. Furthermore, capsaicin synthesized by chilies is thought to be a new and promising therapeutic option in obesity, as it prevents metabolic endotoxemia and systemic chronic low-grade inflammation caused by high-fat diet.
Collapse
Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
| |
Collapse
|
25
|
Gao F, Litchfield B, Wu H. Adipose tissue lymphocytes and obesity. THE JOURNAL OF CARDIOVASCULAR AGING 2024; 4:5. [PMID: 38455510 PMCID: PMC10919906 DOI: 10.20517/jca.2023.38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/09/2024]
Abstract
Obesity is associated with chronic inflammation in adipose tissue (AT), mainly evidenced by infiltration and phenotypic changes of various types of immune cells. Macrophages are the major innate immune cells and represent the predominant immune cell population within AT. Lymphocytes, including T cells and B cells, are adaptive immune cells and constitute another important immune cell population in AT. In obesity, CD8+ effector memory T cells, CD4+ Th1 cells, and B2 cells are increased in AT and promote AT inflammation, while regulatory T cells and Th2 cells, which usually function as immune regulatory or type 2 inflammatory cells, are reduced in AT. Immune cells may regulate the metabolism of adipocytes and other cells through various mechanisms, contributing to the development of metabolic diseases, including insulin resistance and type 2 diabetes. Efforts targeting immune cells and inflammation to prevent and treat obesity-linked metabolic disease have been explored, but have not yielded significant success in clinical studies. This review provides a concise overview of the changes in lymphocyte populations within AT and their potential role in AT inflammation and the regulation of metabolic functions in the context of obesity.
Collapse
Affiliation(s)
- Feng Gao
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Huaizhu Wu
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| |
Collapse
|
26
|
Hildreth AD, Padilla ET, Gupta M, Wong YY, Sun R, Legala AR, O'Sullivan TE. Adipose cDC1s contribute to obesity-associated inflammation through STING-dependent IL-12 production. Nat Metab 2023; 5:2237-2252. [PMID: 37996702 DOI: 10.1038/s42255-023-00934-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 10/18/2023] [Indexed: 11/25/2023]
Abstract
Obesity is associated with chronic low-grade white adipose tissue (WAT) inflammation that can contribute to the development of insulin resistance in mammals. Previous studies have identified interleukin (IL)-12 as a critical upstream regulator of WAT inflammation and metabolic dysfunction during obesity. However, the cell types and mechanisms that initiate WAT IL-12 production remain unclear. Here we show that conventional type 1 dendritic cells (cDC1s) are the cellular source of WAT IL-12 during obesity through analysis of mouse and human WAT single-cell transcriptomic datasets, IL-12 reporter mice and IL-12p70 protein levels by enzyme-linked immunosorbent assay. We demonstrate that cDC1s contribute to obesity-associated inflammation by increasing group 1 innate lymphocyte interferon-γ production and inflammatory macrophage accumulation. Inducible depletion of cDC1s increased WAT insulin sensitivity and systemic glucose tolerance during diet-induced obesity. Mechanistically, endocytosis of apoptotic bodies containing self-DNA by WAT cDC1s drives stimulator of interferon genes (STING)-dependent IL-12 production. Together, these results suggest that WAT cDC1s act as critical regulators of adipose tissue inflammation and metabolic dysfunction during obesity.
Collapse
Affiliation(s)
- Andrew D Hildreth
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA
| | - Eddie T Padilla
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Meha Gupta
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Yung Yu Wong
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Ryan Sun
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Akshara R Legala
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
| |
Collapse
|
27
|
Zaher K, Basingab F. Interaction between Gut Microbiota and Dendritic Cells in Colorectal Cancer. Biomedicines 2023; 11:3196. [PMID: 38137417 PMCID: PMC10741039 DOI: 10.3390/biomedicines11123196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/07/2023] [Accepted: 11/14/2023] [Indexed: 12/24/2023] Open
Abstract
Colorectal cancer (CRC) is a malignancy that manifests in serial stages and has been observed to have an escalating incidence in modern societies, causing a significant global health problem. The development of CRC is influenced by various exogenous factors, including lifestyle, diet, nutrition, environment, and microbiota, that can affect host cells, including immune cells. Various immune dysfunctions have been recognized in patients with CRC at different stages of this disease. The signature of microbiota in the development of CRC-inflammation related to obesity, diet, and reactive host cells, such as dendritic cells (DCs)-has been highlighted by many studies. This study focuses on DCs, the primary cellular mediators linking innate and adaptive immune responses against cancer. In addition, this review focuses on the role of microbiota in dysbiosis and how it affects DCs and, in turn, the immune response and progression of CRC by stimulating different sets of T cells. Additionally, DCs' role in protecting this delicate balance is examined. This is to determine how gene yields of commensal microbiota may be critical in restoring this balance when disrupted. The stages of the disease and major checkpoints are discussed, as well as the role of the C-type lectin receptor of immature DCs pattern recognition receptor in CRC. Finally, based on a thorough examination of worldwide clinical studies and recent advancements in cancer immunotherapy, it is recommended that innovative approaches that integrate DC vaccination strategies with checkpoint inhibitors be considered. This approach holds great promise for improving CRC management.
Collapse
Affiliation(s)
- Kawther Zaher
- Immunology Unit, King Fahad Medical Research Centre, King Abdulaziz University, Jeddah 21859, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21859, Saudi Arabia
| | - Fatemah Basingab
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21585, Saudi Arabia
| |
Collapse
|
28
|
Zhao Q, Wu J, Ding Y, Pang Y, Jiang C. Gut microbiota, immunity, and bile acid metabolism: decoding metabolic disease interactions. LIFE METABOLISM 2023; 2:load032. [PMID: 39872860 PMCID: PMC11749371 DOI: 10.1093/lifemeta/load032] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 07/14/2023] [Accepted: 07/21/2023] [Indexed: 01/03/2025]
Abstract
In recent decades, the global prevalence of metabolic syndrome has surged, posing a significant public health challenge. Metabolic disorders, encompassing diabetes, obesity, nonalcoholic fatty liver disease, and polycystic ovarian syndrome, have been linked to alterations in the gut microbiota. Nonetheless, the connection between gut microbiota and host metabolic diseases warrants further investigation. In this review, we delve into the associations between various metabolic disorders and the gut microbiota, focusing on immune responses and bile acid (BA) metabolism. Notably, T helper cells, innate lymphoid cells, macrophages, and dendritic cells have been shown to modulate host metabolism through interactions with intestinal microorganisms and the release of cytokines. Furthermore, secondary BA metabolites, derived from the microbiota, are involved in the pathogenesis of metabolic diseases via the farnesoid X receptor and Takeda G protein-coupled receptor 5. By covering both aspects of this immune system-microorganism axis, we present a comprehensive overview of the roles played by the gut microbiota, microbiota-derived BA metabolites, and immune responses in metabolic diseases, as well as the interplay between these systems.
Collapse
Affiliation(s)
- Qixiang Zhao
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Jiayu Wu
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Yong Ding
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Yanli Pang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Changtao Jiang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
- Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| |
Collapse
|
29
|
Schleh MW, Caslin HL, Garcia JN, Mashayekhi M, Srivastava G, Bradley AB, Hasty AH. Metaflammation in obesity and its therapeutic targeting. Sci Transl Med 2023; 15:eadf9382. [PMID: 37992150 PMCID: PMC10847980 DOI: 10.1126/scitranslmed.adf9382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 08/29/2023] [Indexed: 11/24/2023]
Abstract
Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive immune system are markedly changed in obesity, implicating these cells in a range of processes linking immune memory to metabolic regulation. Furthermore, weight loss and weight cycling have unexpected effects on adipose tissue immune populations. Here, we review the current literature on the roles of various immune cells in lean and obese adipose tissue. Within this context, we discuss pharmacological and nonpharmacological approaches to obesity treatment and their impact on systemic inflammation.
Collapse
Affiliation(s)
- Michael W. Schleh
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Heather L. Caslin
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Jamie N. Garcia
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Mona Mashayekhi
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Gitanjali Srivastava
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Weight Loss Center, Vanderbilt University Medical Center, Nashville, TN 37204 USA
| | - Anna B. Bradley
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Weight Loss Center, Vanderbilt University Medical Center, Nashville, TN 37204 USA
- VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA
| | - Alyssa H. Hasty
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA
| |
Collapse
|
30
|
Guo C, Chi H. Immunometabolism of dendritic cells in health and disease. Adv Immunol 2023; 160:83-116. [PMID: 38042587 PMCID: PMC11086980 DOI: 10.1016/bs.ai.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2023]
Abstract
Dendritic cells (DCs) are crucial mediators that bridge the innate and adaptive immune responses. Cellular rewiring of metabolism is an emerging regulator of the activation, migration, and functional specialization of DC subsets in specific microenvironments and immunological conditions. DCs undergo metabolic adaptation to exert immunogenic or tolerogenic effects in different contexts. Also, beyond their intracellular metabolic and signaling roles, metabolites and nutrients mediate the intercellular crosstalk between DCs and other cell types, and such crosstalk orchestrates DC function and immune responses. Here, we provide a comprehensive review of the metabolic regulation of DC biology in various contexts and summarize the current understanding of such regulation in directing immune homeostasis and inflammation, specifically with respect to infections, autoimmunity, tolerance, cancer, metabolic diseases, and crosstalk with gut microbes. Understanding context-specific metabolic alterations in DCs may identify mechanisms for physiological and pathological functions of DCs and yield potential opportunities for therapeutic targeting of DC metabolism in many diseases.
Collapse
Affiliation(s)
- Chuansheng Guo
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Hongbo Chi
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States.
| |
Collapse
|
31
|
Burwitz BJ, Yusova S, Robino JJ, Takahashi D, Luo A, Slayden OD, Bishop CV, Hennebold JD, Roberts CT, Varlamov O. Western-style diet in the presence of elevated circulating testosterone induces adipocyte hypertrophy without proinflammatory responses in rhesus macaques. Am J Reprod Immunol 2023; 90:e13773. [PMID: 37766405 PMCID: PMC10544858 DOI: 10.1111/aji.13773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 08/18/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
PROBLEM Anovulatory infertility is commonly associated with hyperandrogenemia (elevated testosterone, T), insulin resistance, obesity, and white adipose tissue (WAT) dysfunction associated with adipocyte hypertrophy. However, whether hyperandrogenemia and adipocyte hypertrophy per se induce a proinflammatory response is unknown. METHOD OF STUDY Young adult female rhesus macaques were exposed to an obesogenic Western-style diet (WSD) in the presence of elevated circulating testosterone (T+WSD) or a low-fat control diet with no exogenous T. Immune cells residing in visceral omental white adipose tissue (OM-WAT), corpus luteum and the contralateral ovary, endometrium, lymph nodes, bone marrow, and peripheral blood mononuclear cells were characterized by flow cytometry during the luteal phase of the reproductive cycle. RESULTS Following one year of treatment, T+WSD animals became more insulin-resistant and exhibited increased body fat and adipocyte hypertrophy compared to controls. T+WSD treatment did not induce macrophage polarization toward a proinflammatory phenotype in the tissues examined. Additionally, T+WSD treatment did not affect TNFα production by bone marrow macrophages in response to toll-like receptor agonists. While the major lymphoid subsets were not significantly affected by T+WSD treatment, we observed a significant reduction in the frequency of effector memory CD8+ T-cells (Tem) in OM-WAT, but not in other tissues. Notably, OM-WAT Tem frequencies were negatively correlated with insulin resistance as assessed by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). CONCLUSION This study shows that short-term T+WSD treatment induces weight gain, insulin resistance, and adipocyte hypertrophy, but does not have a significant effect on systemic and tissue-resident proinflammatory markers, suggesting that adipocyte hypertrophy and mild hyperandrogenemia alone are not sufficient to induce a proinflammatory response.
Collapse
Affiliation(s)
- Benjamin J. Burwitz
- Divisions of Pathobiology and Immunology
- Divisions of Metabolic Health and Disease
| | | | | | | | - Addie Luo
- Reproductive and Developmental Sciences, Oregon National Primate Research Center
| | - Ov D. Slayden
- Reproductive and Developmental Sciences, Oregon National Primate Research Center
| | - Cecily V. Bishop
- Reproductive and Developmental Sciences, Oregon National Primate Research Center
- Department of Animal and Rangeland Sciences, Oregon State University, Corvallis, OR 97331, USA
| | - Jon D. Hennebold
- Reproductive and Developmental Sciences, Oregon National Primate Research Center
| | - Charles T. Roberts
- Divisions of Metabolic Health and Disease
- Reproductive and Developmental Sciences, Oregon National Primate Research Center
| | | |
Collapse
|
32
|
Kaushik A, Chopra D, Kaur K, Gupta S, Chopra P. Serum Adiponectin Levels as an Independent Marker of Severity of Psoriasis: A Cross-Sectional Analysis. JOURNAL OF PSORIASIS AND PSORIATIC ARTHRITIS 2023; 8:148-155. [PMID: 39301471 PMCID: PMC11361544 DOI: 10.1177/24755303231199995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/22/2024]
Abstract
Background Adiponectin is an adipokine, having anti-inflammatory properties, the levels of which are reduced in metabolic syndrome. In psoriasis, it plays a preventive role by inhibiting the differentiation and proliferation of keratinocytes and decreasing the levels of the signature cytokine, IL-17. Aims and objectives To find a correlation between serum adiponectin levels and the severity of psoriasis and to compare these levels amongst patients with parameters of metabolic syndrome vs those without it. Materials and methods This was a cross-sectional observational study consisting of 60 cases of chronic plaque type psoriasis and 20 controls. Mild, moderate and severe disease was defined based on Psoriasis Area Severity Index (PASI). Serum samples were analyzed for fasting serum adiponectin levels. Results The mean serum adiponectin level among cases (16.07 ± 8.55 μg/ml) was significantly lower than controls (21.65 ± 8.07 μg/ml, P = .012). It was not only lower among cases with MetS (14.28 ± 7.95 μg/ml), but also in patients without MetS (17.35 ± 8.83 μg/ml). Serum adiponectin levels were negatively correlated to age, Body Mass Index (BMI), PASI, disease duration and Erythrocyte Sedimentation Rate(ESR). However, only the negative correlation with PASI (P = .000), duration (P = .005) and ESR (P = .010), was statistically significant. Conclusion Serum adiponectin is decreased in psoriasis, independent of metabolic syndrome and is negatively correlated with disease severity and duration. Limitations Analysis on a larger sample size and response to treatment could not be assessed.
Collapse
Affiliation(s)
- Aarushi Kaushik
- Department of Dermatology, Hindu Rao Hospital, New Delhi, India
| | - Dimple Chopra
- Department of Dermatology, Government Medical College, Patiala, India
| | - Karamjot Kaur
- Department of Dermatology, Government Medical College, Patiala, India
| | - Sharang Gupta
- Department of Dermatology, Government Medical College, Patiala, India
| | - Preeyati Chopra
- Department of Dermatology, Government Medical College, Patiala, India
| |
Collapse
|
33
|
Soysouvanh F, Rousseau D, Bonnafous S, Bourinet M, Strazzulla A, Patouraux S, Machowiak J, Farrugia MA, Iannelli A, Tran A, Anty R, Luci C, Gual P. Osteopontin-driven T-cell accumulation and function in adipose tissue and liver promoted insulin resistance and MAFLD. Obesity (Silver Spring) 2023; 31:2568-2582. [PMID: 37724058 DOI: 10.1002/oby.23868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 06/20/2023] [Accepted: 06/26/2023] [Indexed: 09/20/2023]
Abstract
OBJECTIVE This study investigated the contribution of osteopontin/secreted phosphoprotein 1 (SPP1) to T-cell regulation in initiation of obesity-driven adipose tissue (AT) inflammation and macrophage infiltration and the subsequent impact on insulin resistance (IR) and metabolic-associated fatty liver disease (MAFLD) development. METHODS SPP1 and T-cell marker expression was evaluated in AT and liver according to type 2 diabetes and MAFLD in human individuals with obesity. The role of SPP1 on T cells was evaluated in Spp1-knockout mice challenged with a high-fat diet. RESULTS In humans with obesity, elevated SPP1 expression in AT was parallel to T-cell marker expression (CD4, CD8A) and IR. Weight loss reversed AT inflammation with decreased SPP1 and CD8A expression. In liver, elevated SPP1 expression correlated with MAFLD severity and hepatic T-cell markers. In mice, although Spp1 deficiency did not impact obesity, it did improve AT IR associated with prevention of proinflammatory T-cell accumulation at the expense of regulatory T cells. Spp1 deficiency also decreased ex vivo helper T cell, subtype 1 (Th1) polarization of AT CD4+ and CD8+ T cells. In addition, Spp1 deficiency significantly reduced obesity-associated liver steatosis and inflammation. CONCLUSIONS Current findings highlight a critical role of SPP1 in the initiation of obesity-driven chronic inflammation by regulating accumulation and/or polarization of T cells. Early targeting of SPP1 could be beneficial for IR and MAFLD treatment.
Collapse
Affiliation(s)
| | | | | | - Manon Bourinet
- Université Côte d'Azur, INSERM, U1065, C3M, Nice, France
| | | | | | - Jean Machowiak
- Université Côte d'Azur, INSERM, U1065, C3M, Nice, France
| | | | | | - Albert Tran
- Université Côte d'Azur, CHU, INSERM, U1065, C3M, Nice, France
| | - Rodolphe Anty
- Université Côte d'Azur, CHU, INSERM, U1065, C3M, Nice, France
| | - Carmelo Luci
- Université Côte d'Azur, INSERM, U1065, C3M, Nice, France
| | - Philippe Gual
- Université Côte d'Azur, INSERM, U1065, C3M, Nice, France
| |
Collapse
|
34
|
Ramírez-Carreto RJ, Rodríguez-Cortés YM, Torres-Guerrero H, Chavarría A. Possible Implications of Obesity-Primed Microglia that Could Contribute to Stroke-Associated Damage. Cell Mol Neurobiol 2023; 43:2473-2490. [PMID: 36935429 PMCID: PMC10025068 DOI: 10.1007/s10571-023-01329-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 02/14/2023] [Indexed: 03/21/2023]
Abstract
Microglia, the resident macrophages of the central nervous system, are essential players during physiological and pathological processes. Although they participate in synaptic pruning and maintenance of neuronal circuits, microglia are mainly studied by their activity modulating inflammatory environment and adapting their phenotype and mechanisms to insults detected in the brain parenchyma. Changes in microglial phenotypes are reflected in their morphology, membrane markers, and secreted substances, stimulating neighbor glia and leading their responses to control stimuli. Understanding how microglia react in various microenvironments, such as chronic inflammation, made it possible to establish therapeutic windows and identify synergic interactions with acute damage events like stroke. Obesity is a low-grade chronic inflammatory state that gradually affects the central nervous system, promoting neuroinflammation development. Obese patients have the worst prognosis when they suffer a cerebral infarction due to basal neuroinflammation, then obesity-induced neuroinflammation could promote the priming of microglial cells and favor its neurotoxic response, potentially worsening patients' prognosis. This review discusses the main microglia findings in the obesity context during the course and resolution of cerebral infarction, involving the temporality of the phenotype changes and balance of pro- and anti-inflammatory responses, which is lost in the swollen brain of an obese subject. Obesity enhances proinflammatory responses during a stroke. Obesity-induced systemic inflammation promotes microglial M1 polarization and priming, which enhances stroke-associated damage, increasing M1 and decreasing M2 responses.
Collapse
Affiliation(s)
- Ricardo Jair Ramírez-Carreto
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Yesica María Rodríguez-Cortés
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Haydee Torres-Guerrero
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
| | - Anahí Chavarría
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
| |
Collapse
|
35
|
Zhou GL, Xu FJ, Qiao JK, Che ZX, Xiang T, Liu XL, Li XY, Zhao SH, Zhu MJ. E-GWAS: an ensemble-like GWAS strategy that provides effective control over false positive rates without decreasing true positives. Genet Sel Evol 2023; 55:46. [PMID: 37407918 DOI: 10.1186/s12711-023-00820-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 06/23/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) are an effective way to explore genotype-phenotype associations in humans, animals, and plants. Various GWAS methods have been developed based on different genetic or statistical assumptions. However, no single method is optimal for all traits and, for many traits, the putative single nucleotide polymorphisms (SNPs) that are detected by the different methods do not entirely overlap due to the diversity of the genetic architecture of complex traits. Therefore, multi-tool-based GWAS strategies that combine different methods have been increasingly employed. To take this one step further, we propose an ensemble-like GWAS strategy (E-GWAS) that statistically integrates GWAS results from different single GWAS methods. RESULTS E-GWAS was compared with various single GWAS methods using simulated phenotype traits with different genetic architectures. E-GWAS performed stably across traits with different genetic architectures and effectively controlled the number of false positive genetic variants detected without decreasing the number of true positive variants. In addition, its performance could be further improved by using a bin-merged strategy and the addition of more distinct single GWAS methods. Our results show that the numbers of true and false positive SNPs detected by the E-GWAS strategy slightly increased and decreased, respectively, with increasing bin size and when the number and the diversity of individual GWAS methods that were integrated in E-GWAS increased, the latter being more effective than the bin-merged strategy. The E-GWAS strategy was also applied to a real dataset to study backfat thickness in a pig population, and 10 candidate genes related to this trait and expressed in adipose-associated tissues were identified. CONCLUSIONS Using both simulated and real datasets, we show that E-GWAS is a reliable and robust strategy that effectively integrates the GWAS results of different methods and reduces the number of false positive SNPs without decreasing that of true positive SNPs.
Collapse
Affiliation(s)
- Guang-Liang Zhou
- Key Lab of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
| | - Fang-Jun Xu
- Key Lab of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
| | - Jia-Kun Qiao
- Key Lab of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
| | - Zhao-Xuan Che
- Key Lab of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
| | - Tao Xiang
- Key Lab of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xiao-Lei Liu
- Key Lab of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xin-Yun Li
- Key Lab of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, China
| | - Shu-Hong Zhao
- Key Lab of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, China
| | - Meng-Jin Zhu
- Key Lab of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, 430070, China.
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan, 430070, China.
| |
Collapse
|
36
|
Kiran S, Mandal M, Rakib A, Bajwa A, Singh UP. miR-10a-3p modulates adiposity and suppresses adipose inflammation through TGF-β1/Smad3 signaling pathway. Front Immunol 2023; 14:1213415. [PMID: 37334370 PMCID: PMC10272755 DOI: 10.3389/fimmu.2023.1213415] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 05/19/2023] [Indexed: 06/20/2023] Open
Abstract
Background Obesity is a multifactorial disease characterized by an enhanced amount of fat and energy storage in adipose tissue (AT). Obesity appears to promote and maintain low-grade chronic inflammation by activating a subset of inflammatory T cells, macrophages, and other immune cells that infiltrate the AT. Maintenance of AT inflammation during obesity involves regulation by microRNAs (miRs), which also regulate the expression of genes implicated in adipocyte differentiation. This study aims to use ex vivo and in vitro approaches to evaluate the role and mechanism of miR-10a-3p in adipose inflammation and adipogenesis. Methods Wild-type BL/6 mice were placed on normal (ND) and high-fat diet (HFD) for 12 weeks and their obesity phenotype, inflammatory genes, and miRs expression were examined in the AT. We also used differentiated 3T3-L1 adipocytes for mechanistic in vitro studies. Results Microarray analysis allowed us to identify an altered set of miRs in the AT immune cells and Ingenuity pathway analysis (IPA) prediction demonstrated that miR-10a-3p expression was downregulated in AT immune cells in the HFD group as compared to ND. A molecular mimic of miR-10a-3p reduced expression of inflammatory M1 macrophages, cytokines, and chemokines, including transforming growth factor-beta 1 (TGF-β1), transcription factor Krüppel-like factor 4 (KLF4), and interleukin 17F (IL-17F) and induced expression of forkhead box P3 (FoxP3) in the immune cells isolated from AT of HFD-fed mice as compared to ND. In differentiated 3T3-L1 adipocytes, the miR-10a-3p mimics also reduced expression of proinflammatory genes and lipid accumulation, which plays a role in the dysregulation of AT function. In these cells, overexpression of miR-10a-3p reduced the expression of TGF-β1, Smad3, CHOP-10, and fatty acid synthase (FASN), relative to the control scramble miRs. Conclusion Our findings suggest that miR-10a-3p mimic mediates the TGF-β1/Smad3 signaling to improve metabolic markers and adipose inflammation. This study provides a new opportunity for the development of miR-10a-3p as a novel therapeutic for adipose inflammation, and its associated metabolic disorders.
Collapse
Affiliation(s)
- Sonia Kiran
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Mousumi Mandal
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Ahmed Rakib
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Amandeep Bajwa
- Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Udai P. Singh
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, United States
| |
Collapse
|
37
|
Zhang X, Ohayon-Steckel L, Coppin E, Johny E, Dasari A, Florentin J, Vasamsetti S, Dutta P. Epidermal Growth Factor Receptor in Hepatic Endothelial Cells Suppresses MCP-1-Dependent Monocyte Recruitment in Diabetes. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:1363-1371. [PMID: 36946774 PMCID: PMC10121888 DOI: 10.4049/jimmunol.2200557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 02/27/2023] [Indexed: 03/23/2023]
Abstract
Insulin resistance is a compromised response to insulin in target tissues such as liver. Emerging evidence shows that vascular endothelial cells (ECs) are critical in mediating glucose metabolism. However, how liver ECs can regulate inflammation in the setting of insulin resistance is still unknown. Using genome-wide transcriptome analysis of ECs isolated from diabetic mice, we found enrichment of the genes involved in epidermal growth factor receptor (Egfr) signaling. In line with this, hepatic sinusoidal ECs in diabetic mice had elevated levels of Egfr expression. Interestingly, we found an increased number of hepatic myeloid cells, especially macrophages, and systemic glucose intolerance in Cdh5Cre/+Egfrfl/fl mice lacking Egfr in ECs compared with littermate control mice with type II diabetes. Egfr deficiency upregulated the expression of MCP-1 in hepatic sinusoidal ECs. This resulted in augmented monocyte recruitment and macrophage differentiation in Cdh5Cre/+Egfrfl/fl mice compared with littermate control mice as determined by a mouse model of parabiosis. Finally, MCP-1 neutralization and hepatic macrophage depletion in Cdh5Cre/+Egfrfl/fl mice resulted in a reduced number of hepatic macrophages and ameliorated glucose intolerance compared with the control groups. Collectively, these results demonstrate a protective endothelial Egfr signaling in reducing monocyte-mediated hepatic inflammation and glucose intolerance in type II diabetic mice.
Collapse
Affiliation(s)
- Xinyi Zhang
- Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Lee Ohayon-Steckel
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Emilie Coppin
- Regeneration in Hematopoiesis, Institute for Immunology, TU Dresden, Dresden, Germany
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
| | - Ebin Johny
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Ankush Dasari
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Jonathan Florentin
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Sathish Vasamsetti
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Partha Dutta
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Pittsburgh VA Medical Center-University Drive, University Drive C, Pittsburgh, PA, 15213
| |
Collapse
|
38
|
Barthelemy J, Bogard G, Wolowczuk I. Beyond energy balance regulation: The underestimated role of adipose tissues in host defense against pathogens. Front Immunol 2023; 14:1083191. [PMID: 36936928 PMCID: PMC10019896 DOI: 10.3389/fimmu.2023.1083191] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 01/09/2023] [Indexed: 03/06/2023] Open
Abstract
Although the adipose tissue (AT) is a central metabolic organ in the regulation of whole-body energy homeostasis, it is also an important endocrine and immunological organ. As an endocrine organ, AT secretes a variety of bioactive peptides known as adipokines - some of which have inflammatory and immunoregulatory properties. As an immunological organ, AT contains a broad spectrum of innate and adaptive immune cells that have mostly been studied in the context of obesity. However, overwhelming evidence supports the notion that AT is a genuine immunological effector site, which contains all cell subsets required to induce and generate specific and effective immune responses against pathogens. Indeed, AT was reported to be an immune reservoir in the host's response to infection, and a site of parasitic, bacterial and viral infections. In addition, besides AT's immune cells, preadipocytes and adipocytes were shown to express innate immune receptors, and adipocytes were reported as antigen-presenting cells to regulate T-cell-mediated adaptive immunity. Here we review the current knowledge on the role of AT and AT's immune system in host defense against pathogens. First, we will summarize the main characteristics of AT: type, distribution, function, and extraordinary plasticity. Second, we will describe the intimate contact AT has with lymph nodes and vessels, and AT immune cell composition. Finally, we will present a comprehensive and up-to-date overview of the current research on the contribution of AT to host defense against pathogens, including the respiratory viruses influenza and SARS-CoV-2.
Collapse
Affiliation(s)
| | | | - Isabelle Wolowczuk
- Univ. Lille, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (Inserm), Centre Hospitalier Universitaire de Lille (CHU Lille), Institut Pasteur de Lille, U1019 - UMR 9017 - Center for Infection and Immunity of Lille (CIIL), Lille, France
| |
Collapse
|
39
|
Felipe LA, Bachi ALL, Oliveira MC, Moreira SMBP, Afonso JPR, Lino MEM, Paixão V, Silva CHM, Vieira RP, Vencio S, Jirjos EI, Malheiros CA, Insalaco G, Júnior WRF, Oliveira LVF. Effects of Roux-en-Y gastric bypass on the metabolic profile and systemic inflammatory status of women with metabolic syndrome: randomized controlled clinical trial. Diabetol Metab Syndr 2023; 15:19. [PMID: 36788619 PMCID: PMC9930348 DOI: 10.1186/s13098-023-00986-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 01/25/2023] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND Obesity remains a public health problem worldwide. The high prevalence of this condition in the population raises further concerns, considering that comorbidities are often associated with obesity. Among the comorbidities closely associated with obesity, metabolic syndrome (MS) is particularly important, which potentially increases the risk of manifestation of other disorders, such as the prothrombotic and systemic pro-inflammatory states. METHODS A randomized, controlled clinical trial was performed involving female patients (n = 32) aged between 18 and 65 years, with a clinical diagnosis of MS, with severe obesity undergoing Roux-en-Y gastric bypass (RYGB). The study design followed the Consolidated Standards of Reporting Trials statement (CONSORT). Lipid profile, blood glucose and adipokines (adiponectin, leptin, and resistin) and (cytokines IL-1β, IL-6, IL-17, IL-23, and TNF-α) in blood plasma samples were evaluated before and six months after RYGB. RESULTS Patients undergoing RYGB (BSG) showed a significant improvement from preoperative grade III obesity to postoperative grade I obesity. The results showed that while HDL levels increased, the other parameters showed a significant reduction in their postoperative values when compared not only to the values observed before surgery in the BSG group, but also to the values obtained in the control group (CG). As for systemic inflammatory markers adiponectin, leptin, resistin, IL-1β, IL-6, IL-17, IL-23 and TNF- α it was observed that the levels of resistin and IL-17 in the second evaluation increased significantly when compared to the levels observed in the first evaluation in the CG. In the BSG group, while the levels of adiponectin increased, the levels of the other markers showed significant reductions in the postoperative period, in relation to the respective preoperative levels. The analysis of Spearman's correlation coefficient showed a significant positive correlation between IL-17 and IL-23 in the preoperative period, significant positive correlations between TNF-α and IL-6, TNF-α and IL-17, IL-6 and IL-17, and IL-17 and IL-23 were observed postoperatively. CONCLUSIONS According to our results, the reduction of anthropometric measurements induced by RYGB, significantly improves not only the plasma biochemical parameters (lipid profile and glycemia), but also the systemic inflammatory status of severely obese patients with MS. Trials registration NCT02409160.
Collapse
Affiliation(s)
- Lucenda A Felipe
- Post-Graduation Program in Health Sciences, Santa Casa of Sao Paulo Medical School, Sao Paulo, SP, 01221-010, Brazil
| | - André L L Bachi
- Post-Graduation Program in Health Sciences, Santo Amaro University (UNISA), São Paulo, SP, Brazil
| | - Miriã C Oliveira
- Human Movement and Rehabilitation Post Graduation Program, Evangelical University of Goiás (UniEVANGELICA), Anápolis, GO, Brazil
| | - Sandra M B P Moreira
- Post-Graduation Program in Health Sciences, Santa Casa of Sao Paulo Medical School, Sao Paulo, SP, 01221-010, Brazil
| | - João Pedro R Afonso
- Human Movement and Rehabilitation Post Graduation Program, Evangelical University of Goiás (UniEVANGELICA), Anápolis, GO, Brazil
| | - Maria E M Lino
- Scientific Initiation Program, Evangelical University of Goiás, (UniEVANGELICA), Anápolis, GO, Brazil
| | - Vitória Paixão
- Department of Otorhinolaryngology, ENT Lab, Federal University of São Paulo (UNIFESP), São Paulo, SP, 04021-001, Brazil
| | - Carlos H M Silva
- Human Movement and Rehabilitation Post Graduation Program, Evangelical University of Goiás (UniEVANGELICA), Anápolis, GO, Brazil
| | - Rodolfo P Vieira
- Human Movement and Rehabilitation Post Graduation Program, Evangelical University of Goiás (UniEVANGELICA), Anápolis, GO, Brazil
| | - Sergio Vencio
- Institute of Pharmaceutical Sciences, Goiania, (GO), Brazil
| | - Elias I Jirjos
- Post-Graduation Program in Health Sciences, Santa Casa of Sao Paulo Medical School, Sao Paulo, SP, 01221-010, Brazil
| | - Carlos A Malheiros
- Post-Graduation Program in Health Sciences, Santa Casa of Sao Paulo Medical School, Sao Paulo, SP, 01221-010, Brazil
| | - Giuseppe Insalaco
- Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR), 90146, Palermo, Italy
| | - Wilson R Freitas Júnior
- Post-Graduation Program in Health Sciences, Santa Casa of Sao Paulo Medical School, Sao Paulo, SP, 01221-010, Brazil
| | - Luis V F Oliveira
- Human Movement and Rehabilitation Post Graduation Program, Evangelical University of Goiás (UniEVANGELICA), Anápolis, GO, Brazil.
| |
Collapse
|
40
|
Sun Y, Wang B, Hu Q, Zhang H, Lai X, Wang T, Zhao C, Wang J, Zhang X, Niu Q, He B, Jiang E, Shi M, Feng X, Luo Y. Loss of Lkb1 in CD11c + myeloid cells protects mice from diet-induced obesity while enhancing glucose intolerance and IL-17/IFN-γ imbalance. Cell Mol Life Sci 2023; 80:63. [PMID: 36781473 PMCID: PMC9925521 DOI: 10.1007/s00018-023-04707-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/04/2023] [Accepted: 01/22/2023] [Indexed: 02/15/2023]
Abstract
Adipose tissue CD11c+ myeloid cell is an independent risk factor associated with obesity and metabolic disorders. However, the underlying molecular basis remains elusive. Here, we demonstrated that liver kinase B1 (Lkb1), a key bioenergetic sensor, is involved in CD11c+ cell-mediated immune responses in diet-induced obesity. Loss of Lkb1 in CD11c+ cells results in obesity resistance but lower glucose tolerance, which accompanies tissue-specific immune abnormalities. The accumulation and CD80's expression of Lkb1 deficient adipose-tissue specific dendritic cells but not macrophages is restrained. Additionally, the balance of IL-17A and IFN-γ remarkably tips towards the latter in fat T cells and CD11c- macrophages. Mechanistically, IFN-γ promotes apoptosis of preadipocytes and inhibits their adipogenesis while IL-17A promotes the adipogenesis in vitro, which might account in part for the fat gain resistant phenotype. In summary, these findings reveal that Lkb1 is essential for fat CD11c+ dendritic cells responding to HFD exposure and provides new insights into the IL-17A/IFN-γ balance in HFD-induced obesity.
Collapse
Affiliation(s)
- Yunyan Sun
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Institutes of Health Science, Tianjin, 301600, China.,Department of Hematology, Hematology Research Center of Yunnan Province, The First Affiliated Hospital of Kunming Medical University, Kunming, China.,Department of Hematology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, Kunming, China
| | - Bing Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Institutes of Health Science, Tianjin, 301600, China
| | - Qianwen Hu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Institutes of Health Science, Tianjin, 301600, China.,Department of Hematology, Hematology Research Center of Yunnan Province, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Haixiao Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Institutes of Health Science, Tianjin, 301600, China
| | - Xun Lai
- Department of Hematology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, Kunming, China
| | - Tier Wang
- Department of Hematology, Hematology Research Center of Yunnan Province, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chunxiao Zhao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Institutes of Health Science, Tianjin, 301600, China
| | - Jiali Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Institutes of Health Science, Tianjin, 301600, China
| | - Xi Zhang
- Department of Hematology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Center, Kunming, China
| | - Qing Niu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Institutes of Health Science, Tianjin, 301600, China
| | - Baolin He
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China.,Tianjin Institutes of Health Science, Tianjin, 301600, China
| | - Erlie Jiang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China. .,Tianjin Institutes of Health Science, Tianjin, 301600, China.
| | - Mingxia Shi
- Department of Hematology, Hematology Research Center of Yunnan Province, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
| | - Xiaoming Feng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China. .,Tianjin Institutes of Health Science, Tianjin, 301600, China.
| | - Yuechen Luo
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, 300020, China. .,Tianjin Institutes of Health Science, Tianjin, 301600, China.
| |
Collapse
|
41
|
English J, Orofino J, Cederquist CT, Paul I, Li H, Auwerx J, Emili A, Belkina A, Cardamone D, Perissi V. GPS2-mediated regulation of the adipocyte secretome modulates adipose tissue remodeling at the onset of diet-induced obesity. Mol Metab 2023; 69:101682. [PMID: 36731652 PMCID: PMC9922684 DOI: 10.1016/j.molmet.2023.101682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 01/22/2023] [Indexed: 02/01/2023] Open
Abstract
OBJECTIVE Dysfunctional, unhealthy expansion of white adipose tissue due to excess dietary intake is a process at the root of obesity and Type 2 Diabetes development. The objective of this study is to contribute to a better understanding of the underlying mechanism(s) regulating the early stages of adipose tissue expansion and adaptation to dietary stress due to an acute, high-fat diet (HFD) challenge, with a focus on the communication between adipocytes and other stromal cells. METHODS We profiled the early response to high-fat diet exposure in wildtype and adipocyte-specific GPS2-KO (GPS2-AKO) mice at the cellular, tissue and organismal level. A multi-pronged approach was employed to disentangle the complex cellular interactions dictating tissue remodeling, via single-cell RNA sequencing and FACS profiling of the stromal fraction, and semi-quantitative proteomics of the adipocyte-derived exosomal cargo after 5 weeks of HFD feeding. RESULTS Our results indicate that loss of GPS2 in mature adipocytes leads to impaired adaptation to the metabolic stress imposed by HFD feeding. GPS2-AKO mice are significantly more inflamed, insulin resistant, and obese, compared to the WT counterparts. At the cellular level, lack of GPS2 in adipocytes impacts upon other stromal populations, with both the eWAT and scWAT depots exhibiting changes in the immune and non-immune compartments that contribute to an increase in inflammatory and anti-adipogenic cell types. Our studies also revealed that adipocyte to stromal cell communication is facilitated by exosomes, and that transcriptional rewiring of the exosomal cargo is crucial for tissue remodeling. Loss of GPS2 results in increased expression of secreted factors promoting a TGFβ-driven fibrotic microenvironment favoring unhealthy tissue remodeling and expansion. CONCLUSIONS Adipocytes serve as an intercellular signaling hub, communicating with the stromal compartment via paracrine signaling. Our study highlights the importance of proper regulation of the 'secretome' released by energetically stressed adipocytes at the onset of obesity. Altered transcriptional regulation of factors secreted via adipocyte-derived exosomes (AdExos), in the absence of GPS2, contributes to the establishment of an anti-adipogenic, pro-fibrotic adipose tissue environment, and to hastened progression towards a metabolically dysfunctional phenotype.
Collapse
Affiliation(s)
- Justin English
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
| | - Joseph Orofino
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
| | - Carly T. Cederquist
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
| | - Indranil Paul
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; Center for Network Systems Biology, Boston University, Boston, MA, USA.
| | - Hao Li
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.
| | - Johan Auwerx
- Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.
| | - Andrew Emili
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; Center for Network Systems Biology, Boston University, Boston, MA, USA.
| | - Anna Belkina
- Flow Cytometry Core Facility, Boston University School of Medicine, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
| | - Dafne Cardamone
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
| | - Valentina Perissi
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; School of Life Science, Northwestern Polytechnical University, Xi'an 710072, China.
| |
Collapse
|
42
|
Zi C, Wang D, Gao Y, He L. The role of Th17 cells in endocrine organs: Involvement of the gut, adipose tissue, liver and bone. Front Immunol 2023; 13:1104943. [PMID: 36726994 PMCID: PMC9884980 DOI: 10.3389/fimmu.2022.1104943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
T Helper 17 (Th17) cells are adaptive immune cells that play myriad roles in the body. Immune-endocrine interactions are vital in endocrine organs during pathological states. Th17 cells are known to take part in multiple autoimmune diseases over the years. Current evidence has moved from minimal to substantial that Th17 cells are closely related to endocrine organs. Diverse tissue Th17 cells have been discovered within endocrine organs, including gut, adipose tissue, liver and bone, and these cells are modulated by various secretions from endocrine organs. Th17 cells in these endocrine organs are key players in the process of an array of metabolic disorders and inflammatory conditions, including obesity, insulin resistance, nonalcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), osteoporosis and inflammatory bowel disease (IBD). We reviewed the pathogenetic or protective functions played by Th17 cells in various endocrine tissues and identified potential regulators for plasticity of it. Furthermore, we discussed the roles of Th17 cells in crosstalk of gut-organs axis.
Collapse
Affiliation(s)
- Changyan Zi
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Die Wang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yongxiang Gao
- School of International Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China,*Correspondence: Yongxiang Gao, ; Lisha He,
| | - Lisha He
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China,*Correspondence: Yongxiang Gao, ; Lisha He,
| |
Collapse
|
43
|
|
44
|
Liu XH, Zhang Y, Chang L, Wei Y, Huang N, Zhou JT, Cheng C, Zhang J, Xu J, Li Z, Li X. Apolipoprotein A-IV reduced metabolic inflammation in white adipose tissue by inhibiting IKK and JNK signaling in adipocytes. Mol Cell Endocrinol 2023; 559:111813. [PMID: 36341820 DOI: 10.1016/j.mce.2022.111813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/13/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022]
Abstract
Apolipoprotein A-IV (ApoA-IV) plays a role in satiation and serum lipid transport. In diet-induced obesity (DIO) C57BL/6J mice, ApoA-IV deficiency induced in ApoA-IV-/-knock-out (KO mice) resulted in increased bodyweight, insulin resistance (IR) and plasma free fatty acid (FFA), which was partially reversed by stable ApoA-IV-green fluorescent protein (KO-A4-GFP) transfection in KO mice. DIO KO mice exhibited increased M1 macrophages in epididymal white adipose tissue (eWAT) as well as in the blood. Based on RNA-sequencing analyses, cytokine-cytokine receptor interactions, T cell and B cell receptors, and especially IL-17 and TNF-α, were up-regulated in eWAT of DIO ApoA-IV KO compared with WT mice. Supplemented ApoA-IV suppressed lipopolysaccharide (LPS)-induced IKK and JNK phosphorylation in Raw264.7 macrophage cell culture assays. When the culture medium was supplemented to 3T3-L1 adipocytes they exhibited an increased sensitivity to insulin. ApoA-IV protects against obesity-associated metabolic inflammation mainly through suppression in M1 macrophages of eWAT, IL17-IKK and IL17-JNK activity.
Collapse
Affiliation(s)
- Xiao-Huan Liu
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital, Xi'an Jiaotong University, Western China Science & Technology Innovation Harbour, Xi'an, China
| | - Yupeng Zhang
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital, Xi'an Jiaotong University, Western China Science & Technology Innovation Harbour, Xi'an, China; Department of Gastrointestinal Surgery, the Affiliated Taian City Central Hospital, Qingdao University, Taian, China
| | - Liao Chang
- Bio-evidence Science Academy, Xi'an Jiaotong University, Key Laboratory of Ministry of Public Health for Forensic Sciences, Western China Science & Technology Innovation Harbour, Xi'an, China
| | - Yang Wei
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital, Xi'an Jiaotong University, Western China Science & Technology Innovation Harbour, Xi'an, China
| | - Na Huang
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital, Xi'an Jiaotong University, Western China Science & Technology Innovation Harbour, Xi'an, China
| | - Jin-Ting Zhou
- Bio-evidence Science Academy, Xi'an Jiaotong University, Key Laboratory of Ministry of Public Health for Forensic Sciences, Western China Science & Technology Innovation Harbour, Xi'an, China
| | - Cheng Cheng
- Bio-evidence Science Academy, Xi'an Jiaotong University, Key Laboratory of Ministry of Public Health for Forensic Sciences, Western China Science & Technology Innovation Harbour, Xi'an, China
| | - Jianbo Zhang
- Bio-evidence Science Academy, Xi'an Jiaotong University, Key Laboratory of Ministry of Public Health for Forensic Sciences, Western China Science & Technology Innovation Harbour, Xi'an, China
| | - Jing Xu
- Division of Endocrinology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zongfang Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital, Xi'an Jiaotong University, Western China Science & Technology Innovation Harbour, Xi'an, China.
| | - Xiaoming Li
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital, Xi'an Jiaotong University, Western China Science & Technology Innovation Harbour, Xi'an, China.
| |
Collapse
|
45
|
Rakib A, Kiran S, Mandal M, Singh UP. MicroRNAs: a crossroad that connects obesity to immunity and aging. Immun Ageing 2022; 19:64. [PMID: 36517853 PMCID: PMC9749272 DOI: 10.1186/s12979-022-00320-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022]
Abstract
Obesity is characterized by an elevated amount of fat and energy storage in the adipose tissue (AT) and is believed to be the root cause of many metabolic diseases (MDs). Obesity is associated with low-grade chronic inflammation in AT. Like obesity, chronic inflammation and MDs are prevalent in the elderly. The resident immune microenvironment is not only responsible for maintaining AT homeostasis but also plays a crucial role in stemming obesity and related MDs. Mounting evidence suggests that obesity promotes activation in resident T cells and macrophages. Additionally, inflammatory subsets of T cells and macrophages accumulated into the AT in combination with other immune cells maintain low-grade chronic inflammation. microRNAs (miRs) are small non-coding RNAs and a crucial contributing factor in maintaining immune response and obesity in AT. AT resident T cells, macrophages and adipocytes secrete various miRs and communicate with other cells to create a potential effect in metabolic organ crosstalk. AT resident macrophages and T cells-associated miRs have a prominent role in regulating obesity by targeting several signaling pathways. Further, miRs also emerged as important regulators of cellular senescence and aging. To this end, a clear link between miRs and longevity has been demonstrated that implicates their role in regulating lifespan and the aging process. Hence, AT and circulating miRs can be used as diagnostic and therapeutic tools for obesity and related disorders. In this review, we discuss how miRs function as biomarkers and impact obesity, chronic inflammation, and aging.
Collapse
Affiliation(s)
- Ahmed Rakib
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Sonia Kiran
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Mousumi Mandal
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA
| | - Udai P Singh
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN, 38163, USA.
| |
Collapse
|
46
|
Anti-Inflammatory Mechanisms of Dietary Flavones: Tapping into Nature to Control Chronic Inflammation in Obesity and Cancer. Int J Mol Sci 2022; 23:ijms232415753. [PMID: 36555392 PMCID: PMC9779861 DOI: 10.3390/ijms232415753] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/07/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Flavones are natural phytochemicals broadly distributed in our diet. Their anti-inflammatory properties provide unique opportunities to control the innate immune system and inflammation. Here, we review the role of flavones in chronic inflammation with an emphasis on their impact on the molecular mechanisms underlying inflammatory diseases including obesity and cancer. Flavones can influence the innate immune cell repertoire restoring the immune landscape. Flavones impinge on NF-κB, STAT, COX-2, or NLRP3 inflammasome pathways reestablishing immune homeostasis. Devoid of adverse side effects, flavones could present alternative opportunities for the treatment and prevention of chronic inflammation that contributes to obesity and cancer.
Collapse
|
47
|
Qian X, Meng X, Zhang S, Zeng W. Neuroimmune regulation of white adipose tissues. FEBS J 2022; 289:7830-7853. [PMID: 34564950 DOI: 10.1111/febs.16213] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 08/21/2021] [Accepted: 09/24/2021] [Indexed: 01/14/2023]
Abstract
The white adipose tissues (WAT) are located in distinct depots throughout the body. They serve as an energy reserve, providing fatty acids for other tissues via lipolysis when needed, and function as an endocrine organ to regulate systemic metabolism. Their activities are coordinated through intercellular communications among adipocytes and other cell types such as residential and infiltrating immune cells, which are collectively under neuronal control. The adipocytes and immune subtypes including macrophages/monocytes, eosinophils, neutrophils, group 2 innate lymphoid cells (ILC2s), T and B cells, dendritic cells (DCs), and natural killer (NK) cells display cellular and functional diversity in response to the energy states and contribute to metabolic homeostasis and pathological conditions. Accumulating evidence reveals that neuronal innervations control lipid deposition and mobilization via regulating lipolysis, adipocyte size, and cellularity. Vice versa, the neuronal innervations and activity are influenced by cellular factors in the WAT. Though the literature describing adipose tissue cells is too extensive to cover in detail, we strive to highlight a selected list of neuronal and immune components in this review. The cell-to-cell communications and the perspective of neuroimmune regulation are emphasized to enlighten the potential therapeutic opportunities for treating metabolic disorders.
Collapse
Affiliation(s)
- Xinmin Qian
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Xia Meng
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Shan Zhang
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Wenwen Zeng
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China.,Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, China
| |
Collapse
|
48
|
Noh JY, Herrera M, Patil BS, Tan XD, Wright GA, Sun Y. The expression and function of growth hormone secretagogue receptor in immune cells: A current perspective. Exp Biol Med (Maywood) 2022; 247:2184-2191. [PMID: 36151745 PMCID: PMC9899990 DOI: 10.1177/15353702221121635] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The orexigenic hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHS-R), have been extensively studied in the last two decades, revealing that ghrelin signaling has important implications in health and disease. Metabolic diseases, such as obesity and diabetes, are often accompanied by low-grade chronic inflammation, that has been coined as "meta-inflammation." Immune cells are key cellular mediators of meta-inflammation, controlling both initiation and resolution of inflammation. Immune cells exhibit dynamic changes in cellular characteristics and functional output in response to the stimuli/insults from their surrounding microenvironment. Emerging evidence shows that ghrelin has an important effect on inflammation, in addition to its well-known effects on metabolism. However, the cellular/molecular mechanism of ghrelin signaling in immunity is largely unknown because the knowledge in regard to the expression and function of GHS-R in immune cells is currently sparse. In this review, we have accumulated the recent findings related to the expression and functions of GHS-R in various immune cells under different physiological and pathological states. This review aims to inspire further investigation of the immunological roles of ghrelin signaling and advance the therapeutic applications of ghrelin signaling in meta-inflammation.
Collapse
Affiliation(s)
- Ji Yeon Noh
- Department of Nutrition, Texas A&M
University, College Station, TX 77843, USA
| | - Matthew Herrera
- Department of Nutrition, Texas A&M
University, College Station, TX 77843, USA
| | - Bhimanagouda S Patil
- Vegetable and Fruit Improvement Center,
Department of Horticultural Sciences, Texas A&M University, College Station, TX
77843, USA
| | - Xiao-Di Tan
- Department of Pediatrics, Feinberg
School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Gus A Wright
- Department of Veterinary Pathobiology,
Texas A&M University, College Station, TX 77843, USA
| | - Yuxiang Sun
- Department of Nutrition, Texas A&M
University, College Station, TX 77843, USA
- USDA/ARS Children’s Nutrition Research
Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030,
USA
| |
Collapse
|
49
|
Yan K, Zhang P, Jin J, Chen X, Guan H, Li Y, Li H. Integrative analyses of hub genes and their association with immune infiltration in adipose tissue, liver tissue and skeletal muscle of obese patients after bariatric surgery. Adipocyte 2022; 11:190-201. [PMID: 35412419 PMCID: PMC9009953 DOI: 10.1080/21623945.2022.2060059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Bariatric surgery (BS) is an effective treatment for obesity. Adipose tissue, liver tissue and skeletal muscle are important metabolic tissues. This study investigated hub genes and their association with immune infiltration in these metabolic tissues of obese patients after BS by bioinformatic analysis with Gene Expression Omnibus datasets. Differentially expressed genes (DEGs) were identified, and a protein–protein interaction network was constructed to identify hub genes. As a result, 121 common DEGs were identified and mainly enriched in cytokine–cytokine receptor interactions, chemokine signaling pathway, neutrophil activation and immune responses. Immune cell infiltration analysis showed that the abundance of M1 macrophages was significantly lower in adipose and liver tissue after BS (p<0.05). Ten hub genes (TYROBP, TLR8, FGR, NCF2, HCK, CCL2, LAPTM5, MNDA and S100A9) that were all downregulated after BS were also associated with immune cells. Consistently, results in the validated dataset showed that the expression levels of these hub genes were increased in obese patients and mice, and decreased after BS. In conclusion, this study analysed the potential immune and inflammatory mechanisms of BS in three key metabolic tissues of obese patients, and revealed hub genes associated with immune cell infiltration, thus providing potential targets for obesity treatment.
Collapse
Affiliation(s)
- Kemin Yan
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Pengyuan Zhang
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jiewen Jin
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xin Chen
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hongyu Guan
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yanbing Li
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hai Li
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| |
Collapse
|
50
|
Hameed M, Geerling E, Pinto AK, Miraj I, Weger-Lucarelli J. Immune response to arbovirus infection in obesity. Front Immunol 2022; 13:968582. [PMID: 36466818 PMCID: PMC9716109 DOI: 10.3389/fimmu.2022.968582] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 11/04/2022] [Indexed: 12/26/2023] Open
Abstract
Obesity is a global health problem that affects 650 million people worldwide and leads to diverse changes in host immunity. Individuals with obesity experience an increase in the size and the number of adipocytes, which function as an endocrine organ and release various adipocytokines such as leptin and adiponectin that exert wide ranging effects on other cells. In individuals with obesity, macrophages account for up to 40% of adipose tissue (AT) cells, three times more than in adipose tissue (10%) of healthy weight individuals and secrete several cytokines and chemokines such as interleukin (IL)-1β, chemokine C-C ligand (CCL)-2, IL-6, CCL5, and tumor necrosis factor (TNF)-α, leading to the development of inflammation. Overall, obesity-derived cytokines strongly affect immune responses and make patients with obesity more prone to severe symptoms than patients with a healthy weight. Several epidemiological studies reported a strong association between obesity and severe arthropod-borne virus (arbovirus) infections such as dengue virus (DENV), chikungunya virus (CHIKV), West Nile virus (WNV), and Sindbis virus (SINV). Recently, experimental investigations found that DENV, WNV, CHIKV and Mayaro virus (MAYV) infections cause worsened disease outcomes in infected diet induced obese (DIO) mice groups compared to infected healthy-weight animals. The mechanisms leading to higher susceptibility to severe infections in individuals with obesity remain unknown, though a better understanding of the causes will help scientists and clinicians develop host directed therapies to treat severe disease. In this review article, we summarize the effects of obesity on the host immune response in the context of arboviral infections. We have outlined that obesity makes the host more susceptible to infectious agents, likely by disrupting the functions of innate and adaptive immune cells. We have also discussed the immune response of DIO mouse models against some important arboviruses such as CHIKV, MAYV, DENV, and WNV. We can speculate that obesity-induced disruption of innate and adaptive immune cell function in arboviral infections ultimately affects the course of arboviral disease. Therefore, further studies are needed to explore the cellular and molecular aspects of immunity that are compromised in obesity during arboviral infections or vaccination, which will be helpful in developing specific therapeutic/prophylactic interventions to prevent immunopathology and disease progression in individuals with obesity.
Collapse
Affiliation(s)
- Muddassar Hameed
- Department of Biomedical Sciences and Pathobiology, VA-MD Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States
| | - Elizabeth Geerling
- Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO, United States
| | - Amelia K. Pinto
- Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO, United States
| | - Iqra Miraj
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China
| | - James Weger-Lucarelli
- Department of Biomedical Sciences and Pathobiology, VA-MD Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States
| |
Collapse
|